JEFFERSON MEDICAL COLLEGE OF THOMAS JEFFERSON …...Dr. Mark Tykocinski Dean, Jefferson Medical College Dr. Richard G. Pestell Chair, Department of Cancer Biology Mary-Anne Wallace

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JEFFERSON MEDICAL COLLEGE OF THOMAS JEFFERSON UNIVERSITY

THE DEPARTMENT OF CANCER BIOLOGY

ANNUAL REPORT JULY 1, 2010 – JUNE 30, 2011

RICHARD G. PESTELL, M.D., Ph.D. CHAIR

RENATO BASERGA, M.D. VICE CHAIR – RESEARCH

MARJA NEVALAINEN, M.D., Ph.D.

VICE CHAIR – EDUCATION

ERIK KNUDSEN, Ph.D. VICE CHAIR – ACADEMIC AFFAIRS

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Table of Contents Department of Cancer Biology Administration .............................................................................................4

Faculty of the Department of Cancer Biology ...............................................................................................5

Members of the Department of Cancer Biology ...........................................................................................6

Statement of Goals ..................................................................................................................................... 10

Selected Publications.................................................................................................................................. 11

Education .................................................................................................................................................... 14

Joint Seminar Series ............................................................................................................................... 15

Kimmel Cancer Center Grand Rounds .................................................................................................... 20

Faculty Reports ........................................................................................................................................... 22

Andrew E. Aplin, Ph.D. ............................................................................................................................ 23

Renato Baserga, M.D. ............................................................................................................................. 26

Bruno Calabretta, M.D., Ph.D. ................................................................................................................ 28

Mathew C. Casimiro, Ph.D. ..................................................................................................................... 30

Thangavel Chellappagounder, Ph.D. ...................................................................................................... 32

Clay E.S. Comstock, Ph.D. ....................................................................................................................... 33

Ayush Dagvadorj, M.D., Ph.D. ................................................................................................................ 35

Richard L. Davidson, PhD ........................................................................................................................ 36

Stephen R. Dunn ..................................................................................................................................... 37

Adam Ertel, PhD ..................................................................................................................................... 38

Paolo Fortina, MD, PhD .......................................................................................................................... 40

Maxim V. Golovkin, Ph.D. ....................................................................................................................... 43

Linda E. Greenbaum ............................................................................................................................... 44

Xuanmao Jiao, Ph.D. ............................................................................................................................... 50

Xiaoming Ju, M.D. ................................................................................................................................... 52

Karen E. Knudsen .................................................................................................................................... 57

Hilary Koprowski, M.D. ........................................................................................................................... 61

Lucia R. Languino .................................................................................................................................... 63

Zhiping Li ................................................................................................................................................. 64

Jack W. London, Ph.D. ............................................................................................................................ 65

Amy K. McClendon, Ph.D. ....................................................................................................................... 66

Steven B. McMahon Ph.D. ...................................................................................................................... 67

Maria T. Nevalainen, M.D., Ph.D. ........................................................................................................... 71

Marzena J. Pedrini, Ph.D. ........................................................................................................................ 74

Richard G. Pestell, MB, BS, MD, PhD, FACP, FRACP ............................................................................... 75

Andrew A. Quong ................................................................................................................................... 82

Hallgeir Rui, M.D., Ph.D. ......................................................................................................................... 83

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Federica Sotgia, PhD ............................................................................................................................... 88

Fransiscus E. Utama ................................................................................................................................ 93

Kongming Wu ......................................................................................................................................... 94

Zuoren Yu ............................................................................................................................................... 96

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Department of Cancer Biology Administration

Dr. Mark Tykocinski Dean, Jefferson Medical College

Dr. Richard G. Pestell Chair, Department of Cancer Biology Mary-Anne

Wallace Executive Assistant

Atenssa L. Cheek Administrative

Assistant

Donald Seitz Administrative

Assistant

Cecilia Deemer Executive Assistant

Dr. Marja Nevalainen Vice Chair, Education

Dr. Renato Baserga Vice Chair, Research

Richard Haldeman Chief Financial Officer

Dr. Richard Davidson Director of Administration

Jan Rago Pre-Award

Marian Stewart Administrative Assistant

Dr. Steven McMahon Faculty Recruitment

Joan Mello Faculty Affairs

Appointments & Promotions Committee

Beth Gosnell Administrative Assistant Dina Leibowitz

Administrative Assistant/Timekeeper

Joshua Lubin Administrator Post-Award

Dr. Erik Knudsen Vice Chair, Academic Affairs

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Faculty of the Department of Cancer Biology Name Title/Rank Lab/Supervisor

Mathew Casimiro Assistant Professor Pestell

Clay Comstock Assistant Professor K. Knudsen

Stephen R. Dunn Assistant Professor Cancer Biology-Fac

Zhiping Li Assistant Professor Pestell

Federica Sotgia Assistant Professor Lisanti

Chenguang Wang Assistant Professor Cancer Biology-Fac

Kongming Wu Assistant Professor Pestell

* Wen-Shuz Yeow Assistant Professor E.Knudsen

Zuoren Yu Assistant Professor Pestell

Andrew Aplin Associate Professor Cancer Biology-Fac

Maxim V. Golvkin Associate Professor Cancer Biology-Fac

Linda Greenbaum Associate Professor Cancer Biology-Fac

D. Craig Hooper Associate Professor Cancer Biology-Fac

Marja Nevalainen Associate Professor Cancer Biology-Fac

Andrew Quong Associate Professor Cancer Biology-Fac

Renato Baserga Professor Cancer Biology-Fac

Bruno Calabretta Professor Cancer Biology-Fac

Paolo Fortina Professor Cancer Biology-Fac

Erik Knudsen Professor Cancer Biology-Fac

Karen Knudsen Professor Cancer Biology-Fac

* Hilary Koprowski Professor Cancer Biology-Fac

Lucia R. Languino Professor Cancer Biology-Fac

Jack London Professor Cancer Biology-Fac

Steven Mc Mahon Professor Cancer Biology-Fac

Hallgeir Rui Professor Cancer Biology-Fac

Richard Pestell Professor and Chairman Cancer Biology-Fac

Thangavel Chellappagounder Research Instructor E. Knudsen

Ayush Dagvadorj Research Instructor Nevalainen

Adam Ertel Research Instructor Quong

Xuanmao Jiao Research Instructor Pestell

Xiaoming Ju Research Instructor Pestell

Amy Mc Clendon Research Instructor E.Knudsen

Sarmistha Mukherjee Research Instructor Greenbaum

Marzena Pedrini (Fabis) Research Instructor Hooper

Michael Prosniak Research Instructor Hooper

Sheikh Aejaz Sayeed Research Instructor Languino

Lifeng Tian Research Instructor Pestell

* Fransiscus Utama Research Instructor Rui

Marco Velasco-Velazquez Research Instructor Pestell

* Gang Wei Research Instructor Pestell

Ning Yang Research Instructor Rui

* Jie Zhou Research Instructor Pestell * No longer at Jefferson University as of FY Ending 6/30/2011.

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Members of the Department of Cancer Biology STUDENTS

NAME LABORATORY

Michael Augello K. Knudsen

Ethan Abel Aplin

Sucharitha Balasubramaniam K. Knudsen

Darryll Barkhouse Hooper

Kevin Basile Aplin

Emily Bongiorno Hooper

Ryan Bourgo E. Knudsen

Kelly Bryant Lisanti

Christiane Danilo Lisanti

Jeffry Dean E. Knudsen

Chelain Goodman Rui

Jonathan Goodwin K. Knudsen

Ying-Hui Ko Sotgia

Kevin Johnson Rui

Kristinie Lay Fortina

Justin Lin Rui

Stephanos Pavlides Lisanti

Michael Powell Pestell

Kevin Quann Lisanti

Dayana Rivadeneira E. Knudsen

Amy Ryder Rui

Takahiro Sato Rui

Matthew Schiewer K. Knudsen

Supriya Shah K. Knudsen

Timothy Stanek McMahon

Casey Trimmer Lisanti

Aubrey Watkins Calabretta

POSTDOCTORAL FELLOWS NAME LABORATORY Ke Chen Pestell * Lei Chen Hanyin Cheng Rui Gabriele Disanti Pestell Anindita Dutta Languino Michael Gormley Quong Xiaofang Huang Quong Fred Kaplan Aplin Pragati Katiyar Aplin Mateusz Koptyra Nevalainen Alpana Kumari McMahon * Gaspare La Rocca Emanuele Loro Pestell Huimin Lu Languino Samanta Mariani Calabretta Hestia Mellert Mcmahon * Fnu Nitin Amy Peck (Ryder) Rui Dana Pintilie Greenbaum Randy Schrecengost K. Knudsen Yongping Shao Aplin * Ankur Sharma * Thai Tran Marco Trerotola Languino * Paraskevi Vivia Vogiatzi Michele Weiss Aplin Colin Wynne Quong Yuhua Xue Greenbaum * Qiong Zhang Zhijiu Zhong Quong

* No longer at Jefferson University as of FY Ending 6/30/2011.

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VOLUNTEERS NAME LABORATORY Viswandah U. Akella Quong Michael P. Gormley Quong Salmaan S. Khan Quong Albert Kovatich Rui Anita Mamtami Nevalainen Hesha S. Mellert Mcmahon Hui Meng Pestell/Wang Christos Pavlides Lisanti Nicole D. Raptis Quong Drew Shirley Pestell Angela Soliera Calabretta Yu Wang Lisanti

RESEARCH TECHNICIANS NAME LABORATORY Elyse Amico Nevalainen * Alessandra Audia * Fatu Badiane * David Berman Sara Bisetto Pestell Lisa Brown Greenbaum Stephen Ciment K.Knudsen Neda Dadpey Aplin Marco De Dominici Calabretta Kow Essuman Greenbaum Alana Ferrari Greenbaum Rebecca Galanti Languino Nora Homsi Pestell * Jordan Kaplan Kaitlyn Le Aplin William Ostrander K.Knudsen Anthony Pinto Rui Vanessa Rose Pestell * Roberta Toporovski Jenny Vergalli Calabretta * Min Wang Alicia Yanac Rui * No longer at Jefferson University as of FY Ending 6/30/2011.

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RESEARCH LABORATORY ASSISTANTS Karen Markley Greenbaum Marco Crosariol Pestell Melanie Girondo Rui Leeanne Griffith Languino * Marilyn Laurelli * Melanie Mayberry * Alimatou Minkeu * (Harla) Kelly Pfeiffer * Carla Portocarrero Christopher Reed E.Knudsen * Paulina Westfahl Tiziana De Angelis Baserga * Yuriy Smirnov

RESEARCH ASSOCIATES Robert Brodzik Pestell Lei Gu Nevalainen Jianwei Li Hooper Zhiyong Liao Nevalainen

RESEARCH LABORATORY MANAGERS Rhonda B. Kean Hooper Vanessa Rose Pestell

VISITING RESEARCH SCHOLARS * Yang Liu Daniela Sicoli Pestell


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ADMINISTRATION

Richard Haldeman Chief Financial Officer Richard Davidson Administrative Director * Joy Soleiman Clinical Administrator

Post Award Ops Joshua Lubin Karen Gosik Tracey Kajkowski Dina Leibowitz Melissa McDaid Kathy Wyszynski

Pre-Award Admin Jan Rago Yolanda Crespo Maureen Howard Vida Ignatenkovas Jacqueline Lutz * Nicole Matthews * Kathleen Salmon Jeannine Voll

ADMINISTRATIVE SUPPORT

Atenssa L. Cheek Mary Anne Wallace Cecilia Deemer Melanie Elliott * Christina Galli Christina Golio Mildred Harden

Gillian Hewitt Megan Jones * Suzanne Jones Joan Moreno (Mello) Donald Seitz Marian Stewart

* Deborah Swertloff Erin Tello Valeriy Zheleznyak Elizabeth Gosnell


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Statement of Goals DEPARTMENT OF CANCER BIOLOGY

JEFFERSON MEDICAL COLLEGE

“It is necessary to be involved in the action and passion of your times” “Treat all people with dignity and respect regardless of position.”

“I am recognized for the things I do.” The past fiscal year ending June 30, 2011 was a year that solidified our academic and financial future. Since Dr. Pestell’s arrival in December of 2005, the department has been instrumental in keeping the Cancer Center Support Grant (CCSG) by executing key recruitments and strengthening scientific programs. Despite the economic constraints and the challenging funding environment, the Cancer Biology Department has continued to grow its revenue streams while maintaining a balanced budget.

The Department of Cancer Biology established in December 2005, was created with a mandate to make transformational discoveries of significance for patients with cancer. Sixty new faculty and staff moved to Thomas Jefferson University in the first wave of recruitment for the new department of Cancer Biology. The department now has a total of 36 faculty and 91 staff members. The Cancer Biology Department supports the Kimmel Cancer Center facilities, which in turn provides support for the Jefferson Medical College Research Infrastructure including: personnel and supplies, allowing Jefferson researchers to focus on the activities of science and teaching, and administrative staff and general services, to run the department. HIGHLIGHTS PUBLICATIONS During this fiscal year the Department has published 40 papers, and a number of invited presentations by Cancer Biology faculty members, including representations at national and international meetings. NEW LABORATORY EQUIPMENT During the past year, significant equipment purchases were made in support of new faculty recruits. Among other pieces, state-of-the-art equipment was purchased for carrying out and analyzing the results of genomic and proteomic experiments (Biorad thermocycler, Biorad Versadoc 5000 MP System, Fisher Scientific luminometer), for visualization of cancer cells in culture (Nikon Ti-E inverted, phase contrast, fluorescence microscope and incubation system), and for the transfer of genes into cancer cells (Lonza Nucleofector).

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FUNDING The annualized total grant support of the Cancer Biology Department for Fiscal Year 2011 was $21,829,366. The NIH grant support for the fiscal year was $13,628,632 and the NCI grant support was $10,445,672.

Selected Publications since July 1, 2010

1. Sato T, Neilson LM, Peck AR, Liu C, Tran TH, Witkiewicz A, Hyslop T, Nevalainen MT, Sauter G, Rui

H. Signal transducer and activator of transcription-3 and breast cancer prognosis. Am J Cancer Res. 2011;1(3):347-355.

2. Koptyra M, Gupta S, Talati P, Nevalainen MT. Signal transducer and activator of transcription 5a/b: Biomarker and therapeutic target in prostate and breast cancer. Int J Biochem Cell Biol. 2011 Jun 17. [Epub ahead of print]

3. McClendon AK, Dean JL, Ertel A, Fu Z, Rivadeneira DB, Reed CA, Bourgo RJ, Witkiewicz A, Addya S, Mayhew CN, Grimes HL, Fortina P, Knudsen ES. RB and p53 Cooperate to Prevent Liver Tumorigenesis in Response to Tissue Damage. Gastroenterology. 2011 Jun 23. [Epub ahead of print]

4. Hooper DC, Roy A, Kean RB, Phares TW, Barkhouse DA. Therapeutic immune clearance of rabies virus from the CNS. Future Virol. 2011 Mar 1;6(3):387-397.

5. Abel EV, Aplin AE. Finding the root of the problem: the quest to identify melanoma stem cells. Front Biosci (Schol Ed). 2011 Jun 1;3:937-45.

6. Li J, Faber M, Dietzschold B, Hooper DC. The role of toll-like receptors in the induction of immune responses during rabies virus infection. Adv Virus Res. 2011;79:115-26.

7. Hooper DC, Roy A, Barkhouse DA, Li J, Kean RB. Rabies virus clearance from the central nervous system. Adv Virus Res. 2011;79:55-71.

8. Aplin AE, Kaplan FM, Shao Y. Mechanisms of Resistance to RAF Inhibitors in Melanoma. J Invest Dermatol. 2011 Sep;131(9):1817-20. doi: 10.1038/jid.2011.147.Epub 2011 May 19.

9. DeAngelis T, Wu K, Pestell R, Baserga R. The type 1 insulin-like growth factor receptor and resistance to DACH1. Cell Cycle. 2011 Jun 15;10(12):1956-9. Epub 2011 Jun 15.

10. Zhao S, Yang Y, Liu J, Liu H, Ge N, Yang H, Zhang H, Xing J. Association of mitochondrial DNA content in peripheral blood leukocyte with hepatitis B virus-related hepatocellular carcinoma in a Chinese Han population. Cancer Sci. 2011 Aug;102(8):1553-8. doi: 10.1111/j.1349-7006.2011.01968.x. Epub 2011 Jun 1.

11. Sussman RT, Zhang XY, McMahon SB. Enzymatic assays for assessing histone deubiquitylation activity. Methods. 2011 Jul;54(3):339-47. Epub 2011 Apr 12.

12. Katiyar P, Aplin AE. FOXD3 regulates migration properties and Rnd3 expression in melanoma cells. Mol Cancer Res. 2011 May;9(5):545-52. Epub 2011 Apr 8.

13. Sayeed A, Alam N, Trerotola M, Languino LR. Insulin-like growth factor 1 stimulation of androgen receptor activity requires β(1A) integrins. J Cell Physiol. 2011 Apr 4. doi: 10.1002/jcp.22784. *Epub ahead of print]

14. Bourgo RJ, Ehmer U, Sage J, Knudsen ES. RB deletion disrupts coordination between DNA replication licensing and mitotic entry in vivo. Mol Biol Cell. 2011Apr;22(7):931-9. Epub 2011 Feb 2.

15. Calabretta B, Salomoni P. Inhibition of autophagy: a new strategy to enhancesensitivity of chronic myeloid leukemia stem cells to tyrosine kinase inhibitors. Leuk Lymphoma. 2011 Feb;52 Suppl 1:54-9. Epub 2011 Jan 21. Review.

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16. Llaverias G, Danilo C, Mercier I, Daumer K, Capozza F, Williams TM, Sotgia F, Lisanti MP, Frank PG. Role of cholesterol in the development and progression of breast cancer. Am J Pathol. 2011 Jan;178(1):402-12. Epub 2010 Dec 23.

17. Meng H, Tian L, Zhou J, Li Z, Jiao X, Li WW, Plomann M, Xu Z, Lisanti MP, Wang C, Pestell RG. PACSIN 2 represses cellular migration through direct association with cyclin D1 but not its alternate splice form cyclin D1b. Cell Cycle. 2011 Jan 1;10(1):73-81. Epub 2011 Jan 1.

18. Wang C, Lisanti MP, Liao DJ. Reviewing once more the c-myc and Ras collaboration: converging at the cyclin D1-CDK4 complex and challenging basic concepts of cancer biology. Cell Cycle. 2011 Jan 1;10(1):57-67. Epub 2011 Jan 1.

19. Powell MJ, Casimiro MC, Cordon-Cardo C, He X, Yeow WS, Wang C, McCue PA, McBurney MW, Pestell RG. Disruption of a Sirt1-dependent autophagy checkpoint inthe prostate results in prostatic intraepithelial neoplasia lesion formation. Cancer Res. 2011 Feb 1;71(3):964-75. Epub 2010 Dec 28.

20. Liu M, Sakamaki T, Casimiro MC, Willmarth NE, Quong AA, Ju X, Ojeifo J, JiaoX, Yeow WS, Katiyar S, Shirley LA, Joyce D, Lisanti MP, Albanese C, Pestell RG. The canonical NF-kappaB pathway governs mammary tumorigenesis in transgenic miceand tumor stem cell expansion. Cancer Res. 2010 Dec 15;70(24):10464-73.

21. Iozzo RV, Sanderson RD. Proteoglycans in cancer biology, tumour microenvironment and angiogenesis. J Cell Mol Med. 2011 May;15(5):1013-31. doi: 10.1111/j.1582-4934.2010.01236.x.

22. Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C, Morrissey C, Zhang X, Comstock CE, Witkiewicz AK, Gomella L, Knudsen ES, Nelson PS, Knudsen KE. The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest. 2010 Dec 1;120(12):4478-92. doi: 10.1172/JCI44239. Epub 2010 Nov 22.

23. Weiss MB, Aplin AE. Paying "particle" attention to novel melanoma treatment strategies. J Invest Dermatol. 2010 Dec;130(12):2699-701.

24. Zhou J, Liu Y, Zhang W, Popov VM, Wang M, Pattabiraman N, Suñé C, Cvekl A, Wu K, Jiang J, Wang C, Pestell RG. Transcription elongation regulator 1 is a co-integrator of the cell fate determination factor Dachshund homolog 1. J Biol Chem. 2010 Dec 17;285(51):40342-50. Epub 2010 Oct 18.

25. Johnson KJ, Peck AR, Liu C, Tran TH, Utama FE, Sjolund AB, Schaber JD, Witkiewicz AK, Rui H. PTP1B suppresses prolactin activation of Stat5 in breast cancer cells. Am J Pathol. 2010 Dec;177(6):2971-83. Epub 2010 Oct 15.

26. Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE, Knudsen ES. RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response. Cell Cycle. 2010 Oct 15;9(20):4153-63. Epub 2010 Oct 27.

27. Li Z, Jiao X, Wang C, Shirley LA, Elsaleh H, Dahl O, Wang M, Soutoglou E, Knudsen ES, Pestell RG. Alternative cyclin D1 splice forms differentially regulate the DNA damage response. Cancer Res. 2010 Nov 1;70(21):8802-11. Epub 2010 Oct 12.

28. Wu K, Jiao X, Li Z, Katiyar S, Casimiro MC, Yang W, Zhang Q, Willmarth NE, Chepelev I, Crosariol M, Wei Z, Hu J, Zhao K, Pestell RG. Cell fate determination factor Dachshund reprograms breast cancer stem cell function. J Biol Chem. 2011 Jan 21;286(3):2132-42. Epub 2010 Oct 11.

29. Katiyar S, Casimiro MC, Dettin L, Ju X, Wagner EF, Tanaka H, Pestell RG. C-jun inhibits mammary apoptosis in vivo. Mol Biol Cell. 2010 Dec;21(23):4264-74. Epub 2010 Oct 6.

30. Lidonnici MR, Audia A, Soliera AR, Prisco M, Ferrari-Amorotti G, Waldron T, Donato N, Zhang Y, Martinez RV, Holyoake TL, Calabretta B. Expression of the transcriptional repressor Gfi-1 is regulated by C/EBP{alpha} and is involved in its proliferation and colony formation-inhibitory effects in p210BCR/ABL-expressing cells. Cancer Res. 2010 Oct 15;70(20):7949-59. Epub 2010 Oct 5.

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31. Dagvadorj A, Tan SH, Liao Z, Xie J, Nurmi M, Alanen K, Rui H, Mirtti T, Nevalainen MT. N-terminal truncation of Stat5a/b circumvents PIAS3-mediated transcriptional inhibition of Stat5 in prostate cancer cells. Int J Biochem CellBiol. 2010 Dec;42(12):2037-46. Epub 2010 Sep 18.

32. Kaplan FM, Shao Y, Mayberry MM, Aplin AE. Hyperactivation of MEK-ERK1/2 signaling and resistance to apoptosis induced by the oncogenic B-RAF inhibitor, PLX4720, in mutant N-RAS melanoma cells. Oncogene. 2011 Jan 20;30(3):366-71. Epub 2010 Sep 6.

33. Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C, Whitaker-Menezes D, Daumer KM, Lin Z, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG, Knudsen ES, Sotgia F, Lisanti MP. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle. 2010 Aug 15;9(16):3256-76. Epub 2010 Aug 28.

34. Fortina P, Kricka LJ. Nanotechnology: improving clinical testing? Clin Chem.2010 Sep;56(9):1384-9. 35. La Rocca G, Shi B, Sepp-Lorenzino L, Baserga R. Expression of micro-RNA-145 is regulated by a

highly conserved genomic sequence 3' to the pre-miR. J Cell Physiol. 2011 Mar;226(3):602-7. 36. Trimmer C, Whitaker-Menezes D, Bonuccelli G, Milliman JN, Daumer KM, Aplin AE, Pestell RG,

Sotgia F, Lisanti MP, Capozza F. CAV1 inhibits metastatic potential in melanomas through suppression of the integrin/Src/FAK signaling pathway. Cancer Res. 2010 Oct 1;70(19):7489-99. Epub 2010 Aug 13.

37. Shao Y, Aplin AE. Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells. Cancer Res. 2010 Aug 15;70(16):6670-81. Epub 2010 Jul 20.

38. Frank PG. Endothelial caveolae and caveolin-1 as key regulators of atherosclerosis. Am J Pathol. 2010 Aug;177(2):544-6. Epub 2010 Jun 25.

39. DeAngelis T, Morrione A, Baserga R. Mutual interaction and reciprocal down-regulation between c-met and insulin receptor substrate-1. J Cell Physiol. 2010 Sep;224(3):658-63.

40. Greenbaum LE, Wells RG. The role of stem cells in liver repair and fibrosis.Int J Biochem Cell Biol. 2011 Feb;43(2):222-9. Epub 2009 Nov 13. Review.

There were 40 publications authored by Cancer Biology Members from 07/01/2010 to 06/30/2011.

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Education The Department of Cancer Biology supports: a weekly Seminar Series (Thursdays) Prostate Cancer Symposium a weekly Kimmel Cancer Center Grand

Rounds Celebration of Life

Hepatoma Dinner Symposium Giacchinno Lecture in Cancer Research a weekly Research in Progress Seminar

(Fridays) Sidney Weinhouse memorial lecture

a monthly KCC Translational Research Seminar

Goto Memorial Lecture

Keep Your Rear in Gear 5k Walk Scientific and Clinical Update on Colorectal Cancer Life After A Cancer Diagnosis, Patient and Family Conference There are currently 30 postdoctoral fellows and 27 students. All faculty are asked to participate in educational support of the Medical College.

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Joint Seminar Series Date Series Speaker Title

Friday, September 10, 2010 KCC Research In Progress Seminar Christine Juliana ---

Friday, September 10, 2010 KCC Research In Progress Seminar Sanda Remakus ---

Wednesday, September 22, 2010

Schwartz Center Rounds TBD

Thursday, September 23, 2010 Joint Seminar Series/Microbiology & Immunology/Biochemistry/Cancer Biology/Kimmel Cancer Center

Victor Rizzo, PhD, FAHA Plasma membrane microdomains, redox signaling and vascular inflammation

Friday, September 24, 2010 KCC Research In Progress Seminar Celestine Wanjalla ---

Friday, September 24, 2010 KCC Research In Progress Seminar Thai Tran, PhD ---

Friday, October 01, 2010 KCC Research In Progress Seminar Joseph Comber ---

Friday, October 01, 2010 KCC Research In Progress Seminar Dayana Rivadeneira ---

Thursday, October 14, 2010 Joint Seminar Series/Microbiology & Immunology/Biochemistry/Cancer Biology/Kimmel Cancer Center

David Solit ---

Friday, October 15, 2010 KCC Research In Progress Seminar Elizabeth Rogers ---

Friday, October 15, 2010 KCC Research In Progress Seminar Michael Augello ---


Kerry S. Campbell, PhD Molecular regulation of killer cell Ig-like receptors (KIR) in human NK cells

Friday, October 22, 2010 KCC Research In Progress Seminar Jordan Wesolowski ---

Friday, October 22, 2010 KCC Research In Progress Seminar Tessa Lawrence ---

Wednesday, October 27, 2010 Schwartz Center Rounds TBD


Xin Lin, PhD The role of CARMA family members in immunity and cancer

Friday, October 29, 2010 KCC Research In Progress Seminar Konstantine Halkidis ---

Friday, October 29, 2010 KCC Research In Progress Seminar Takahiro Sato ---

Thursday, November 04, 2010 Joint Seminar Series/Microbiology & Immunology/Biochemistry/Cancer Biology/Kimmel Cancer Center

Robert S. Krauss, PhD

Modeling the holoprosencephaly spectrum in the mouse: Regulation of Sonic hedgehog signaling by co-receptors

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Date Series Speaker Title


Mark Ptashne, PhD Chromatin architecture: what determines it, and does it matter?

Friday, November 12, 2010 KCC Research In Progress Seminar Elliot Goodenough ---

Friday, November 12, 2010 KCC Research In Progress Seminar Nicholas Sicilliano ---


Facundo D. Batista, PhD Dynamic imaging of lymphocyte activation - from single molecules to living tissue

Friday, November 19, 2010 KCC Research In Progress Seminar Lan Huang ---

Friday, November 19, 2010 KCC Research In Progress Seminar Kelly Bryant ---

Wednesday, November 24, 2010


Wednesday, December 22, 2010


Friday, January 07, 2011 KCC Research In Progress Seminar Kevin Basile ---

Friday, January 07, 2011 KCC Research In Progress Seminar Ethan Abel ---

Friday, January 14, 2011 KCC Research In Progress Seminar Heather Montie, PhD ---

Friday, January 21, 2011 KCC Research In Progress Seminar Zenobia Cofer ---

Friday, January 21, 2011 KCC Research In Progress Seminar Supriya Shah ---

Wednesday, January 26, 2011 Schwartz Center Rounds TBD TBD

Friday, February 04, 2011 KCC Research In Progress Seminar Changpo Chen, PhD ---

Friday, February 04, 2011 KCC Research In Progress Seminar Yuanyuan Jin ---

Thursday, February 10, 2011 Joint Seminar Series/Microbiology & Immunology/Biochemistry/Cancer Biology/Kimmel Cancer Center

Yun Qiu, PhD

Mechanisms of therapeutic resistance in prostate cancer: post-transcriptional and post-translational regulation of Androgen Receptor

Friday, February 18, 2011 KCC Research In Progress Seminar Amy Peck, PhD ---

Friday, February 18, 2011 KCC Research In Progress Seminar Darryll Barkhouse ---

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Wednesday, February 23, 2011

Schwartz Center Rounds TBD TBD

Thursday, February 24, 2011 Joint Seminar Series/Microbiology & Immunology/Biochemistry/Cancer Biology/Kimmel Cancer Center

Scott D. Cramer, PhD Use of stem cells to model prostate cancer genetics

Thursday, March 03, 2011 Joint Seminar Series/Microbiology & Immunology/Biochemistry/Cancer Biology/Kimmel Cancer Center

Yihong Ye, PhD Protein quality control at the endoplasmic reticulum: mechanisms and implications for cancer therapy

Friday, March 04, 2011 KCC Research In Progress Seminar Casey Trimmer ---

Friday, March 04, 2011 KCC Research In Progress Seminar Christiane Danilo ---

Monday, March 07, 2011 Joint Faculty Seminar Series Matthias Schnell, PhD "Two birds with one stone? Bivalent vaccines against rabies and Ebola viruses"


Dieter Soll, PhD The Continuing Evolution of the Genetic Code

Friday, March 11, 2011 KCC Research In Progress Seminar Michael Magee ---

Friday, March 11, 2011 KCC Research In Progress Seminar Erin Heine ---

Monday, March 14, 2011 Joint Faculty Seminar Series James Keen, PhD "Searching for sorting mechanisms inside cells: "Gyrating Clathrin"


Amy H. Bouton, PhD Signaling complexes that regulatir of breast tumor cell growth, motility, and therapeutic response

Monday, March 21, 2011 Joint Faculty Seminar Series Catherine E. Calkins, PhD Interferon-gamma, IL-17 and Chronic Hepatitis B

Wednesday, March 23, 2011 Schwartz Center Rounds TBD TBD


Marianne Sadar ---

Monday, March 28, 2011 Joint Faculty Seminar Series D. Craig Hooper, PhD "Immune mechanisms of antibody delivery into the CNS"


William C. Hahn, M.D., PhD Functional genomics, experimental models and cancer

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Thursday, June 02, 2011 Joint Seminar Series/Microbiology & Immunology/Biochemistry/Cancer Biology/Kimmel Cancer Center

Alfred Singer, M.D. How the thymus imposes MHC specificity on developing T cells

Friday, June 03, 2011 KCC Research In Progress Seminar Shixue Shen, Ph.D ---

Friday, June 03, 2011 KCC Research In Progress Seminar Raja S. Reddy Vuyyuru, Ph.D. ---

Friday, June 17, 2011 KCC Research In Progress Seminar Anindita Dutta, Ph.D. ---

Friday, June 17, 2011 KCC Research In Progress Seminar Hanyin Cheng, PhD ---

Friday, April 1, 2011 KCC Research In Progress Seminar Katherine Black ---

Friday, April 1, 2011 KCC Research In Progress Seminar Swati Roy ---

Friday, April 15, 2011 KCC Research In Progress Seminar Xiang Wang ---

Friday, April 29, 2011 KCC Research In Progress Seminar Emily Gomme ---

Friday, April 29, 2011 KCC Research In Progress Seminar Tessa Lawrence ---

Friday, April 8, 2011 KCC Research In Progress Seminar Matthew Martz ---

Friday, April 8, 2011 KCC Research In Progress Seminar Gregory Dickinson ---

Friday, December 10, 2010 KCC Research In Progress Seminar Sucharitha Balasubramaniam ---

Friday, December 3, 2010 KCC Research In Progress Seminar Jessica Gold ---

Friday, May 20, 2011 KCC Research In Progress Seminar Pooja Talati ---

Friday, May 20, 2011 KCC Research In Progress Seminar David Hoang ---

Friday, May 6, 2011 KCC Research In Progress Seminar Angela Conde ---

Monday, April 11, 2011 Joint Faculty Seminar Series Michael Root, PhD "How viral fusion proteins work: an HIV-1 gp41 story"

Monday, April 18, 2011 Joint Faculty Seminar Series Diane Merry, PhD

"The role of functional domains of the androgen receptor in its aggregation and toxicity in the polyglutamine expansion disease spinal and bulbar muscular atrophy"

Monday, April 25, 2011 Joint Faculty Seminar Series Jianke Zhang, PhD "FADD at the crossroads of apoptotic and necrotic signalings"

Monday, April 4, 2011 Joint Faculty Seminar Series James Jaynes, PhD "Defining the chromosomal boundaries of epigenetic gene regulation

Monday, May 2, 2011 Joint Faculty Seminar Series Erica Johnson, Ph.D. "Roles for SUMO in DNA repair"

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Monday, May 9, 2011 Joint Faculty Seminar Series Isidore Rigoutsos, Ph.D. "MicroRNA Target Identification: Truths and Misconceptions"

Thursday, April 14, 2011 Joint Seminar Series/Microbiology & Immunology/Biochemistry/Cancer Biology/Kimmel Cancer Center

Eric Huseby, PhD ---


David B. Solit, M.D. Genetic Predictors of RAF/MEK-dependence


Dr. Paul Monga Beta-catenin signaling in Liver Regeneration and HCC: Sorting the Good from the Bad!


Zoran Culig Different effects of supressors of cytokine signaling in prostate cancer depend on androgen sensitivity

Thursday, December 2, 2010 Joint Seminar Series/Microbiology & Immunology/Biochemistry/Cancer Biology/Kimmel Cancer Center

Patricia Labosky, PhD Regulation of Multipotency by this Tanscription Factor Foxd3

Thursday, December 9, 2010 Joint Seminar Series/Microbiology & Immunology/Biochemistry/Cancer Biology/Kimmel Cancer Center

Gail S. Prins, PhD Early-life Estrogens Reprogram the Prostate Gland and Increase Susceptibility to Adult Carcinogenesis

Thursday, May 19, 2011 Joint Seminar Series/Microbiology & Immunology/Biochemistry/Cancer Biology/Kimmel Cancer Center

Pamela Geyer Expanding transcriptional roles for a classic Drosophila insulator protein


Patrick O'Brien, PhD How the thymus imposes MHC specificity on developing T cells


Mark von Zastrow, M.D., , PhD Regulation of signaling receptors by endocytic membrane traffic

Wednesday, April 27, 2011 Schwartz Center Rounds TBD TBD

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Kimmel Cancer Center Grand Rounds Bluemle Life Sciences Building, 233 South 10th Street, Mandeville Conference Hall, Room 101

Agenda July 2010 to June 2011


Wednesday, September 15, 2010 KCC Grand Rounds Jeffrey A. Sosman, MD TBD

Wednesday, September 29, 2010 KCC Grand Rounds Victor J. Strecher, PhD, MPH TBD

Wednesday, October 13, 2010 KCC Grand Rounds Eileen M. O'Reilly, MD Chemotherapy for Pancreatic Ductal Adenocarcinoma: Current Status and the Future

Wednesday, November 03, 2010 KCC Grand Rounds Nancy E. Davidson, MD TBD

Wednesday, November 17, 2010 KCC Grand Rounds Timothy R. Rebbeck, PhD TBD

Wednesday, January 05, 2011 KCC Grand Rounds Margaret A. Tempero, MD Pancreatic Cancer: Reaching for a Cure

Wednesday, January 19, 2011 KCC Grand Rounds Sergio A. Giralt, MD Myeloma and Transplant Vision for the Next 5 Years

Wednesday, January 26, 2011 KCC Grand Rounds Schwartz Center Rounds ---

Wednesday, February 02, 2011 KCC Grand Rounds Chris Logothetis, MD TBD

Wednesday, February 09, 2011 KCC Grand Rounds Victor J. Strecher, PhD, MPH TBD

Wednesday, March 16, 2011 KCC Grand Rounds Otis Brawley, MD Opportunities for Research on Disparities in Cancer Prevention and Control

Wednesday, March 30, 2011 KCC Grand Rounds William Breitbart, MD End of Life: Balancing Hope and Reality

Wednesday, June 01, 2011 KCC Grand Rounds David A. Scheinberg, MD, Phd TBD

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Wednesday, June 15, 2011 KCC Grand Rounds Harold Moses TBD

Wednesday, June 29, 2011 KCC Grand Rounds Philip N. Tsichlis, MD TBD

Tuesday, May 3, 2011 KCC Grand Rounds Tony Hunter, PhD TBD

Wednesday, April 13, 2011 KCC Grand Rounds Jeffrey S. Miller, M.D. The Role of NK Cells in Cancer and Transplation

Wednesday, April 20, 2011 KCC Grand Rounds Martine Extermann, MD, PhD Aging and Cancer: Interactions and Challenges

Wednesday, December 1, 2010 KCC Grand Rounds Anthony W. Tolcher, MD, FRCP (C)

TBD

Wednesday, May 11, 2011 KCC Grand Rounds Anthony W. Tolcher, MD, FRCP (C) Pharmacodynamic Studies in Phase 1 Studies - Useful Tools or an Expensive Distraction

Wednesday, May 4, 2011 KCC Grand Rounds H. Kim Lyerly, MD TBD

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Faculty Reports

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Andrew E. Aplin, Ph.D. Associate Professor

1. Description of Research Melanoma is the deadliest form of skin cancer. The serine/threonine kinase, B-RAF, is mutated in two-thirds of melanomas and the integrins, αvβ3 and α4β1, are over-expressed. Our goal is to determine the mechanisms by which mutant B-RAF and aberrant integrin-matrix signaling in

melanoma cells contribute to malignant properties such as enhanced proliferation, resistance to apoptosis, and invasion into the dermis. 2. Current Research Projects

Mutant B-RAF signaling in melanoma

Role and regulation of FOXD3

Integrin and extracellular matrix control of melanoma progression 3. Grant Support NIH-R01 GM-067893 08/01/04 - 03/31/14 Adhesion and ERK signaling in melanoma Role: Principal Investigator The major aims of this competitive renewal are to determine roles of Rnd3 and FOXD3 in melanoma cell invasion and whether targeting stromal fibronectin-integrin signaling, in combination with B-RAF, inhibits melanoma cell survival. American Cancer Society RGS #113229 01/01/08 - 12/31/11 Extracellular Matrix and Cell Signaling in Melanoma Role: Principal Investigator The aims of this proposal are to determine the requirement for the integrin signaling pathways and stromal extracellular matrix in the invasive growth of melanoma cells in a skin-mimetic microenvironment. NIH R01 CA125103 08/01/08 - 07/31/13 B-RAF Regulation of the Cell Cycle in Melanoma Role: Principal Investigator The aims of this proposal are to investigate whether up-regulation of Skp2 and proteasomal degradation of MKP3 overcome cell cycle arrest checkpoints during melanoma progression. NIH-ARRA Supplement to GM-067893 08/01/09 - 07/31/10 Adhesion regulation of ERK nucleocytoplasmic trafficking Role: Principal Investigator The aims are to identify importins that control the nucleocytoplasmic trafficking of ERK, determine the mechanism of ERK1/2 regulation of Rnd3, and determine the requirement of B-RAF activity in resistance to anoikis in 3-D models. NCC pre-doctoral fellowship to Rong Hu 09/01/07 - 08/31/09 Skp2 regulation of melanoma cell proliferation

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Role: Mentor American Cancer Society PF #113244 to R. M. Klein 01/01/08 - 12/31/09 Role of Oncogenic B-RAF in Melanoma Migration and Invasion Role: Mentor 4. Future Plans Analysis of mechanisms of resistance to B-RAF inhibitors 5. Committees Ph.D. thesis committee: Richard Christ (mentor, Arthur Buchberg) Jeff Dean (mentor, Erik Knudsen) Casey Trimmer (mentor, Michael Lisanti) Bill Davidson (mentor, Ulrich Rodeck) Sucharitha Balasubramaniam (mentor, Karen Knudsen) 6. Publications

Abel EV, Aplin AE. Finding the root of the problem: the quest to identify melanoma stem cells. Front Biosci (Schol Ed). 2011 Jun 1;3:937-45.

Aplin AE, Kaplan FM, Shao Y. Mechanisms of Resistance to RAF Inhibitors in Melanoma. J Invest Dermatol. 2011 Sep;131(9):1817-20. doi: 10.1038/jid.2011.147. Epub 2011 May 19.

Katiyar P, Aplin AE. FOXD3 regulates migration properties and Rnd3 expression in melanoma cells. Mol Cancer Res. 2011 May;9(5):545-52. Epub 2011 Apr 8.

Aplin AE, Sato T. Mind the BAP. Pigment Cell Melanoma Res. 2011 Feb;24(1):6-7.

Weiss MB, Aplin AE. Paying "particle" attention to novel melanoma treatment strategies. J Invest Dermatol. 2010 Dec;130(12):2699-701.

Trimmer C, Whitaker-Menezes D, Bonuccelli G, Milliman JN, Daumer KM, Aplin AE, Pestell RG, Sotgia F, Lisanti MP, Capozza F. CAV1 inhibits metastatic potential in melanomas through suppression of the integrin/Src/FAK signaling pathway. Cancer Res. 2010 Oct 1;70(19):7489-99. Epub 2010 Aug 13.

Shao Y, Aplin AE. Akt3-mediated resistance to apoptosis in B-RAF-targeted melanoma cells. Cancer Res. 2010 Aug 15;70(16):6670-81. Epub 2010 Jul 20.

Matthies R, Aplin AC, Jarvis AP. Performance of a passive treatment system for net-acidic coal mine drainage over five years of operation. Sci Total Environ. 2010 Sep 15;408(20):4877-85. Epub 2010 Jul 6.

Kaplan FM, Mastrangelo MJ, Aplin AE. The wrath of RAFs: rogue behavior of B-RAF kinase inhibitors. J Invest Dermatol. 2010 Nov;130(11):2669-71. Epub 2010 Jun 24.

7. Book Chapters and Reviews

Abel, E.V. and Aplin (2010) Finding the root of the problem: the quest to identify melanoma cells. Submitted.

Kaplan, F.M., Mastrangelo, M.J. and Aplin, A.E. (2010) The wrath of RAFs: rogue behavior of B-RAF kinase inhibitors. J. Investigative Dermatol. Submitted.

8. Presentations

Oct 2009 Department of Pharmacology, University of Illinois Chicago

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Nov 2009 Jefferson Institute of Molecular Medicine, Departments of Dermatology and Orthopaedic Surgery

Jan 2010 Department of Surgery, Thomas Jefferson University

March 2010 Department Of Biochemistry, University of Iowa

March 2010 Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University

April 2010 Co-chair Introduction to Minisymposium Session ‘Signaling in Tumor Cell Migration and Invasion’ AACR Annual Meeting, Washington D.C.

9. Editorial Positions Editorial advisory panel of Biochemical Journal. 10. Teaching

Seminars in Genetics (GE720 & GE730)

Molecular Basis of Cancer (GE652)

Regulation of Cell Cycle and Apoptosis (GE636)

Protein Function and Dysfunction (BI612)

Mentor for 2 graduate students and 4 post-doctoral fellows 11. Memberships

American Society for Cell Biology

American Association for Cancer Research

PanAmerican Society for Pigment Cell Research

Society for Matrix Biology

Society for Melanoma Research

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Renato Baserga, M.D. Distinguished Professor

1. Description of Research

My research has been focusing for the past 20 years on the type 1 insulin-like growth factor receptor (IGF-IR), a growth factor receptor that plays a major role in growth, differentiation and transformation. Antibodies to the IGF-IR are presently in clinical trials. Many pharma companies and biotechs use reagents (plasmids and cell lines) developed in my laboratory, which are a steady source

of income for our OTT.

2. Current Research Projects We are presently working on 2 projects:

The role of micro RNA 145 in down-regulating the IGF-IR signaling pathway. miR145 targets and down-regulates the IGF-IR and its docking protein, the insulin receptor substrate-1 (IRS-1) and causes a dramatic inhibition of cancer cell growth. The work on miR145 has been done with the collaboration and support of Merck Company.

The mechanism of v-src transformation, which requires the collaboration of the IGF-IR and IRS-1.

3. Grant Support

080-03800-R16719 (National Cancer Institute, NIH) 02/01/2001 – 07/31/2010 Biology of the P53 Protein 080-37038-AF0601 (Tobacco Funds)

4. Future Plans We have isolated a clone of miR145 that produces in cells a mature, functional micro RNA. We have found that its expression is regulated by a highly conserved sequence on 3’ side of the pre-miR. We propose to investigate the mechanism of action of this regulatory element.

5. Committees

Membership Committee, Kimmel Cancer Center

Executive Committee, Kimmel Cancer Center

6. Publications

DeAngelis T, Wu K, Pestell R, Baserga R. The type 1 insulin-like growth factor receptor and resistance to DACH1. Cell Cycle. 2011 Jun 15;10(12):1956-9. Epub 2011 Jun 15.

Baserga R. Self-plagiarism in music and science. Nature. 2011 Feb 3;470(7332):39.

La Rocca G, Shi B, Audia A, Ferrari-Amorotti G, Mellert HS, Calabretta B, McMahon SB, Sepp-Lorenzino L, Baserga R. Regulation of microRNA-145 by growth arrest and differentiation. Exp Cell Res. 2011 Feb 15;317(4):488-95. Epub 2010 Nov 25.

La Rocca G, Shi B, Sepp-Lorenzino L, Baserga R. Expression of micro-RNA-145 is regulated by a highly conserved genomic sequence 3' to the pre-miR. J Cell Physiol. 2011 Mar;226(3):602-7.

DeAngelis T, Morrione A, Baserga R. Mutual interaction and reciprocal down-regulation between c-met and insulin receptor substrate-1. J Cell Physiol. 2010 Sep;224(3):658-63.

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Baserga, R. (2009) Customizing the targeting of the IGF-1 Receptor. Future Oncology, in press

Yu, Z., Baserga, R., Chen, L., Wang, C., Lisanti, M.P. and Pestell, R.G. (in press) micro RNA, Cell Cycle and Human Breast Cancer. Am. J. Pathology

8. Presentations

MedImmune, Osis Corporation

9. Editorial Positions Experimental Cell Research, Journal of Cellular Physiology, American Journal of Pathology

10. Teaching Mentoring for associates of Drs. Pestell, Sato (Ophthalmology) and Doria (Surgery)

11. Memberships Various societies (AAAS, ACS, AAP etc.)

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Bruno Calabretta, M.D., Ph.D. Professor

1. Description of Research The primary research interest in the laboratory is the analysis of the molecular mechanisms responsible for transformation by the BCR/ABL oncogene of the Philadelphia chromosome. In particular, my laboratory is investigating the apoptosis and differentiation-inhibitory effects of BCR/ABL. 2. Current Research Projects

A research project is assessing the role of BCR/ABL in regulating the expression/activity of transcription factor important for normal hematopoiesis (c-Myb, C/EBPalpha, Gfi-1) using in vitro and in vivo models of BCR/ABL-dependent transformation. A second research project is assessing the role of tyrosine kinase inhibitors (TKI) such as the BCR/ABL inhibitor Imatinib in inducing autophagy and how suppression of autophagy by pharmacological and genetic inhibitors enhances TKI-induced cell death of chronic myelogenous leukemia stem cells. 3. Grant Support NCI R01 CA095111 07/17/2002 – 06/30/2011 Transcription Factor Regulation by the BCR/ABL Oncogene 4. Future Plans

June 1, 2010: submission of R01 “Autophagy inhibition and Imatinib sensitivity of CML stem cells”

October 1, 2010: submission of P01 “Cell Survival and Cancer”

February 2011: submission of R01 “Role of Gfi-1 in the biological effects of C/EBPalpha” 5. Committees

Ph.D. in Genetics: “Examination and Admission Committee”

KCC “Membership Committee and Flow Cytometry Committee” 6. Publications

Calabretta B, Salomoni P. Inhibition of autophagy: a new strategy to enhance sensitivity of chronic myeloid leukemia stem cells to tyrosine kinase inhibitors. Leuk Lymphoma. 2011 Feb;52 Suppl 1:54-9. Epub 2011 Jan 21. Review.


Lidonnici MR, Audia A, Soliera AR, Prisco M, Ferrari-Amorotti G, Waldron T, Donato N, Zhang Y, Martinez RV, Holyoake TL, Calabretta B. Expression of the transcriptional repressor Gfi-1 is regulated by C/EBP{alpha} and is involved in its proliferation and colony formation-inhibitory effects in p210BCR/ABL-expressing cells. Cancer Res. 2010 Oct 15;70(20):7949-59. Epub 2010 Oct 5.

Ferrari-Amorotti G, Mariani SA, Novi C, Cattelani S, Pecorari L, Corradini F, Soliera AR, Manzotti G, Fragliasso V, Zhang Y, Martinez RV, Lam EW, Guerzoni C, Calabretta B. The biological effects of C/EBPalpha in K562 cells depend on the potency of the N-terminal

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regulatory region, not on specificity of the DNA binding domain. J Biol Chem. 2010 Oct 1;285(40):30837-50. Epub 2010 Jul 20.

Tanno B, Sesti F, Cesi V, Bossi G, Ferrari-Amorotti G, Bussolari R, Tirindelli D, Calabretta B, Raschellà G. Expression of Slug is regulated by c-Myb and is required for invasion and bone marrow homing of cancer cells of different origin. J Biol Chem. 2010 Sep 17;285(38):29434-45. Epub 2010 Jul 11.

7. Presentations

MRC Toxicology Unit, Leicester, UK, September 22, 2009: “Role of c-Myb in BCR/ABL-dependent B-ALL”

8. Editorial Positions Editorial Board of American Journal of Pathology and Cancer Research 9. Teaching:

First year Medical Students - Molecular Basis of disease (5 lectures)

First year Pharmacy Students - (3 lectures)

First year Ph.D. students - Core Course in “Fundamentals in Biology” (2 lectures)

Second year Ph.D. students - Course Director of “Cell Cycle and Apoptosis” 10. Memberships

American Society of Hematology


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Mathew C. Casimiro, Ph.D. Assistant Professor

Description of Research Cyclin D1 is a gatekeeper which controls exit from G1 state into S phase. It partners with the cyclin dependent kinases to promote phosphorylation of the retinoblastoma protein thus releasing the transcription factors of the E2F family to promote DNA synthesis. The cyclin D1 gene is amplified in approximately 30% of human breast adenocarcinomas, and the protein is reportedly overexpressed in 60 to 80% of all cases. In mice localized

overexpression of cyclin D1 is sufficient to induce mammary tumors. We have recently described a novel function of cyclin D1 in controlling mitochondrial function and size. Mitochondrial activity assayed by Mitotracker staining was enhanced by genetic deletion or antisense or small interfering RNA to cyclin D1. Global gene expression profiling and functional analysis of mammary epithelium cell-targeted cyclin D1 antisense transgenics demonstrated that cyclin D1 inhibits mitochondrial activity and down regulates a key component of glycolysis, namely Hexokinase II. Thus in addition to regulating nuclear DNA synthesis, cyclin D1 also regulates mitochondrial function in vivo, coordinating metabolic substrate utilization within the cell. The implications this novel function of cyclin D1 has on normal cellular function and in cancer are currently being investigated. Current Research Projects Cyclin D1 and mitochondrial function. ErbB2 oncogenic signaling and the role of Notch in progenitor cell maintenance. Future plans Future work includes defining the metabolic consequences of mis-regulated cyclin D1 expression in breast cancer. By applying a number of biochemical assays including ATP, NAD/NADH ratio, oxygen consumption and a metabolic profiling screen we intend to characterize the metabolic changes induced by cyclin D1. Publications

Velasco-Velázquez MA, Li Z, Casimiro M, Loro E, Homsi N, Pestell RG. Examining the role of cyclin D1 in breast cancer. Future Oncol. 2011 Jun;7(6):753-65.

Bryant KG, Camacho J, Jasmin JF, Wang C, Addya S, Casimiro MC, Fortina P, Balasubramaniam S, Knudsen KE, Schwarting R, Lisanti MP, Mercier I. Caveolin-1 overexpression enhances androgen-dependent growth and proliferation in the mouse prostate. Int J Biochem Cell Biol. 2011 Sep;43(9):1318-29. Epub 2011 May 12.

Powell MJ, Casimiro MC, Cordon-Cardo C, He X, Yeow WS, Wang C, McCue PA, McBurney MW, Pestell RG. Disruption of a Sirt1-dependent autophagy checkpoint in the prostate results in prostatic intraepithelial neoplasia lesion formation. Cancer Res. 2011 Feb 1;71(3):964-75. Epub 2010 Dec 28.

Liu M, Sakamaki T, Casimiro MC, Willmarth NE, Quong AA, Ju X, Ojeifo J, Jiao X, Yeow WS, Katiyar S, Shirley LA, Joyce D, Lisanti MP, Albanese C, Pestell RG. The canonical NF-kappaB pathway governs mammary tumorigenesis in transgenic mice and tumor stem cell expansion. Cancer Res. 2010 Dec 15;70(24):10464-73.

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Wu K, Jiao X, Li Z, Katiyar S, Casimiro MC, Yang W, Zhang Q, Willmarth NE, Chepelev I, Crosariol M, Wei Z, Hu J, Zhao K, Pestell RG. Cell fate determination factor Dachshund reprograms breast cancer stem cell function. J Biol Chem. 2011 Jan 21;286(3):2132-42. Epub 2010 Oct 11.

Katiyar S, Casimiro MC, Dettin L, Ju X, Wagner EF, Tanaka H, Pestell RG. C-jun inhibits mammary apoptosis in vivo. Mol Biol Cell. 2010 Dec;21(23):4264-74. Epub 2010 Oct 6.

Chiavarina B, Whitaker-Menezes D, Migneco G, Martinez-Outschoorn UE, Pavlides S, Howell A, Tanowitz HB, Casimiro MC, Wang C, Pestell RG, Grieshaber P, Caro J, Sotgia F, Lisanti MP. HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: Autophagy drives compartment-specific oncogenesis. Cell Cycle. 2010 Sep 1;9(17):3534-51. Epub 2010 Sep 4.

Pavlides S, Tsirigos A, Migneco G, Whitaker-Menezes D, Chiavarina B, Flomenberg N, Frank PG, Casimiro MC, Wang C, Pestell RG, Martinez-Outschoorn UE, Howell A, Sotgia F, Lisanti MP. The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle. 2010 Sep 1;9(17):3485-505.

Casimiro MH, Gil MH, Leal JP. Suitability of gamma irradiated chitosan based membranes as matrix in drug release system. Int J Pharm. 2010 Aug 16;395(1-2):142-6. Epub 2010 May 26.

Oña-Burgos P, Casimiro M, Fernández I, Navarro AV, Fernández Sánchez JF, Carretero AS, Gutiérrez AF. Octahedral iron(II) phthalocyanine complexes: multinuclear NMR and relevance as NO(2) chemical sensors. Dalton Trans. 2010 Jul 21;39(27):6231-8. Epub 2010 Jun 3.

Committees PhD thesis committee member for C. Glass

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Thangavel Chellappagounder, Ph.D. Research Instructor

Publications

Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, Clarke R, Knudsen ES. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer. Endocr Relat Cancer. 2011 Apr 28;18(3):333-45. Print 2011.

Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C, Morrissey C, Zhang X, Comstock CE, Witkiewicz AK, Gomella L,

Knudsen ES, Nelson PS, Knudsen KE. The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest. 2010 Dec 1;120(12):4478-92. doi: 10.1172/JCI44239. Epub 2010 Nov 22.

Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene. 2010 Jul 15;29(28):4018-32. Epub 2010 May 17.

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Clay E.S. Comstock, Ph.D. Assistant Professor

Description of Research & Future plans Aberrant expression and localization of Cyclin D1 in Prostate Cancer. My research is to understand the complex interplay between important cell cycle regulatory factors and their contribution to prostate cancer using cell/animal models, and human specimens. Specifically, cyclin D1 is an important cell cycle regulatory protein that has been shown to modulate prostate cancer cell growth through its ability to promote cell cycle progression and to modulate the activity of the androgen receptor. Thus,

cyclin D1 is able to balance the strength and duration of the primary growth signal in prostate cancer. Based on this, it was speculated that disruption of cyclin D1 action in prostate cancer could yield a proliferative advantage through increased AR activity. To this end, we identified that cyclin D1 is aberrantly regulated in the majority of human prostate cancer specimens. The consequence of aberreanr cyclin D1 is not known, evidence suggests that loss of cyclin D1 may enhance androgen receptor activity. My current focus is to identify the mechanisms that result in aberrant cyclin D1 in prostate cancer. Long term, I hope to identify cell cycle specific theraputics that impact prostate cancer progression. Current research projects Transcriptional regulation of the androgen receptor by cyclin D1.

Grant Support Submitted NIH CA139349-01A1 Mechanism: R21 Principal Investigator: Clay Comstock DOD PC094507 Mechanism: New Investigator Principal Investigator: Clay Comstock Publications

Riggs T, Saini AP, Comstock CH, Lee W. Comparison of cardiac Z-score with cardiac asymmetry for prenatal screening of congenital heart disease. Ultrasound Obstet Gynecol. 2011 Mar 11. [Epub ahead of print]

Comstock CH. Coping with changes in health care. Am J Obstet Gynecol. 2011 Mar;204(3):256-8.

Levy DE, Byfield SD, Comstock CB, Garber JE, Syngal S, Crown WH, Shields AE. Underutilization of BRCA1/2 testing to guide breast cancer treatment: black and Hispanic women particularly at risk. Genet Med. 2011 Apr;13(4):349-55.

Dixit SS, Kim H, Comstock C, Faris GW. Near infrared transillumination imaging of breast cancer with vasoactive inhalation contrast. Biomed Opt Express. 2010 Jul 27;1(1):295-309.

Comstock CH. The antenatal diagnosis of placental attachment disorders. Curr Opin Obstet Gynecol. 2011 Apr;23(2):117-22. Review.

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Comstock CE, Augello MA, Schiewer MJ, Karch J, Burd CJ, Ertel A, Knudsen ES, Jessen WJ, Aronow BJ, Knudsen KE. Cyclin D1 is a selective modifier of androgen-dependent signaling and androgen receptor function. J Biol Chem. 2011 Mar 11;286(10):8117-27. Epub 2011 Jan 5.

Comstock C. Breast magnetic resonance imaging interpretation using computer-aided detection. Semin Roentgenol. 2011 Jan;46(1):76-85.

Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C, Morrissey C, Zhang X, Comstock CE, Witkiewicz AK, Gomella L, Knudsen ES, Nelson PS, Knudsen KE. The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest. 2010 Dec 1;120(12):4478-92. doi: 10.1172/JCI44239. Epub 2010 Nov 22.

Espinoza J, Lee W, Comstock C, Romero R, Yeo L, Rizzo G, Paladini D, ViÃ±als F, Achiron R, Gindes L, Abuhamad A, Sinkovskaya E, Russell E, Yagel S. Collaborative study on 4-dimensional echocardiography for the diagnosis of fetal heart defects: the COFEHD study. J Ultrasound Med. 2010 Nov;29(11):1573-80.

Memberships Sigma Xi

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Ayush Dagvadorj, M.D., Ph.D. Research Instructor


The main focus of my research is identifying the role of Prolactin (Prl)-Janus kinase 2 (Jak2)-Signal Transducer and Activator of Transcription 5 (Stat5) pathway in castration-resistant and metastatic prostate cancer cells.

I have first-authored/co-authored papers showing that 1) Autocrine prolactin promotes prostate cancer cell growth via Jak-2-Stat5a/b

signaling pathway, 2) Transcription factor Stat5a/b synergizes with androgen receptor in prostate cancer cells, 3) Stat5a/b promotes growth of human prostate cancer cells in vitro and in vivo, 4) Transcription factor Stat3 stimulates metastatic behavior of human prostate cancer cells in vivo, whereas Stat5b has a preferential role in the promotion of prostate cancer cell viability and tumor growth, 5) developed a new human prostate cancer cell line, CWR22Pc, which is regulated by androgens and expresses high levels of androgen receptor and prostate specific antigen (PSA). These cells are able to form tumors in nude mice, and when androgens are withdrawn, the tumors initially shrink and then recur as castration-resistant tumors, mimicking human prostate cancer, 6) Truncation of Stat5a/b circumvents PIAS3-mediated transcriptional inhibition of Stat5 in prostate cancer cells. 2. Current Research Projects Currently, I am working on a project identifying the molecular mechanism of androgen receptor dependent Stat5a/b activation in prostate cancer cells, sensitization of prostate cancer cells to radiation through Stat5a/b inhibition and genetic changes of Stat5 in prostate cancer. 3. Publications

Dagvadorj A, Tan SH, Liao Z, Xie J, Nurmi M, Alanen K, Rui H, Mirtti T, Nevalainen MT. N-terminal truncation of Stat5a/b circumvents PIAS3-mediated transcriptional inhibition of Stat5 in prostate cancer cells. Int J Biochem Cell Biol. 2010 Dec;42(12):2037-46. Epub 2010 Sep 18.

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Richard L. Davidson, PhD Research Professor

Current Academic Appointment: Research Professor, Department of Cancer Biology, Jefferson Medical College, Thomas Jefferson University Future Plans: Administrator, Clinical and Translational Science Award Committees: Research Compliance Committee, 2003-Present

Chair, Cancer Center Membership Committee, 2005-Present University Research Advisory Committee, 2008- Present Steering Committee, Clinical and Translational Science Award application Memberships: American Association for the Advancement of Science

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Stephen R. Dunn Assistant Professor

1. Description of Research: provide support for research in the Core Facility in Cancer Genomics. Research is varied and includes support work in human clinical research and mouse models of cancer.

2. Current Research Projects: (1) Characterization of genomic polymorphisms, which associate with phenotypes of obesity and hypertension in African Americans. (2) Seeking CLIA certification for complex molecular, multi-analyte diagnostic tests in patients enrolled in clinical trial. (3) K-Ras and BRAF genetic testing

3. Grant Support: (1) Commonwealth of PA Dept. of HEA. (2) Nucleic Acid Facility Core Grant. (3) various sponsors

4. Future Plans: Continue to provide support in the way of robotics, DNA extraction, TAQman assays, sequencing, OpenArray.

5. Publications:

Sharma K, Ix JH, Mathew AV, Cho M, Pflueger A, Dunn SR, Francos B, Sharma S, Falkner B, McGowan TA, Donohue M, Ramachandrarao S, Xu R, Fervenza FC, Kopp JB. Pirfenidone for diabetic nephropathy. J Am Soc Nephrol. 2011 Jun;22(6):1144-51. Epub 2011 Apr 21.

Pernice M, Dunn SR, Miard T, Dufour S, Dove S, Hoegh-Guldberg O. Regulation of apoptotic mediators reveals dynamic responses to thermal stress in the reef building coral Acropora millepora. PLoS One. 2011 Jan 24;6(1):e16095.

Hann HW, Dunn SR, Ahn M, Park SY. Question of ALT flare during switch to adefovir from lamivudine: A single center open-label, randomized, safety study (June 17, 2005 to February 5, 2009). J Med Virol. 2010 Sep;82(9):1489-93.

Huan Y, DeLoach S, Daskalakis C, Dunn SR, Sharma K, Falkner B. Regulation of transforming growth factor-beta1 by insulin in prediabetic African Americans. Kidney Int. 2010 Aug;78(3):318-24. Epub 2010 Apr 14.

6. Teaching: training of Renal Fellow in molecular techniques

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Adam Ertel, PhD Research Instructor

Current Academic Appointment Research Instructor, Cancer Biology Secondary Appointment Description of Research My research focuses on the modes of gene regulation and gene interactions that can be inferred from large collections of mRNA expression data. This approach is useful for identifying normal

interaction and regulatory connections between genes as well as the disruption of these connections in complex diseases such as cancer. Bioinformatics approaches allow these connections to be easily extended into the context of biological pathways in order to understand global chances in the presence of disease. One particular pathway where this approach is being applied is the retinoblastoma tumor suppressor pathway, which is disrupted in a majority of human cancers. Gene interactions in the retinoblastoma pathway are presently being explored in the context of breast, liver, and prostate cancer. Gene interactions revealed by large-scale mRNA expression profiles can also be used to explore the effects of genetic variation. I am applying this approach for the combination of gene expression and genome-wide association studies to identify how genotypic and copy number variations play a role in the biological pathways that contribute to colorectal and other types of cancer. Current Research Projects

1. Association between the retinoblastoma gene expression signature and clinical Outcome in breast cancer

2. Evaluating molecular profiles for drug therapy-relevant stratification of breast cancer

3. The impact of DNA copy number variation on colorectal cancer recurrance and survival

Publications

McClendon AK, Dean JL, Ertel A, Fu Z, Rivadeneira DB, Reed CA, Bourgo RJ, Witkiewicz A, Addya S, Mayhew CN, Grimes HL, Fortina P, Knudsen ES.. RB and p53 Cooperate to Prevent Liver Tumorigenesis in Response to Tissue Damage.. Gastroenterology. 2011 Jun 24. [Epub ahead of print]

Villa N, Bentivegna A, Ertel A, Redaelli S, Colombo C, Nacinovich R, Broggi F, Lissoni S, Bungaro S, Addya S, Fortina P, DalprÃ L.. A de novo supernumerary genomic discontinuous ring chromosome 21 in a child with mild intellectual disability.. Am J Med Genet A. 2011 Jun;155A(6):1425-31. Epub 2011 May 13.

Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK, Birbe RC, Howell A, Pavlides S, Gandara R, Pestell RG, Sotgia F, Philp NJ, Lisanti MP.. Evidence for a stromal-epithelial lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts.". Cell Cycle. 2011 Jun 1;10(11):1772-83. Epub 2011 Jun 1.

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Witkiewicz AK, Kline J, Queenan M, Brody JR, Tsirigos A, Bilal E, Pavlides S, Ertel A, Sotgia F, Lisanti MP.. Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers.. Cell Cycle. 2011 Jun 1;10(11):1794-809. Epub 2011 Jun 1.

Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, Wang C, Flomenberg N, Knudsen ES, Howell A, Pestell RG, Sotgia F, Lisanti MP.. Ketones and lactate increase cancer cell stemness. Cell Cycle. 2011 Apr 15;10(8):1271-86.

Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, Wang C, Flomenberg N, Knudsen ES, Howell A, Pestell RG, Sotgia F, Lisanti MP.. Ketones and lactate increase cancer cell stemness. Cell Cycle. 2011 Apr 15;10(8). [Epub ahead of print]

Thangavel C, Dean JL, Ertel A, Knudsen KE, Aldaz CM, Witkiewicz AK, Clarke R, Knudsen ES.. Therapeutically activating RB: reestablishing cell cycle control in endocrine therapy-resistant breast cancer.. Endocr Relat Cancer. 2011 Apr 28;18(3):333-45. Print 2011.

Comstock CE, Augello MA, Schiewer MJ, Karch J, Burd CJ, Ertel A, Knudsen ES, Jessen WJ, Aronow BJ, Knudsen KE.. Cyclin D1 is a selective modifier of androgen-dependent signaling and androgen receptor function.. J Biol Chem. 2011 Mar 11;286(10):8117-27. Epub 2011 Jan 5.

Martinez Cantarin MP, Ertel A, Deloach S, Fortina P, Scott K, Burns TL, Falkner B.. Variants in genes involved in functional pathways associated with hypertension in African Americans.. Clin Transl Sci. 2010 Dec;3(6):279-86.

Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C, Morrissey C, Zhang X, Comstock CE, Witkiewicz AK, Gomella L, Knudsen ES, Nelson PS, Knudsen KE.. The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression.. J Clin Invest. 2010 Dec 1;120(12):4478-92. Epub 2010 Nov 22.

Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE, Knudsen ES.. RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response.. Cell Cycle. 2010 Oct 15;9(20):4153-63. Epub 2010 Oct 27.

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Paolo Fortina, MD, PhD Professor

1. Description of Research As Director of the Laboratory of Cancer Genomics, I provide state-of-the-art molecular assays and expertise to facilitate projects in basic, translational and clinical research. By serving as a centralized resource with a variety of platforms for genome-wide, gene-targeted and next-generation sequencing studies, the Laboratory of Cancer Genomics offers a wide spectrum of services including nucleic acid extraction, DNA sequence analysis, mutation detection, multiplex SNP genotyping,

genome-wide association studies, linkage analysis and copy number variation studies as well as genome-wide and targeted mRNA and microRNA expression profilings. Expanded services include DNA-, RNA- and microRNA-sequencing on a next-generation sequencing (NGS) platform, target-enrichment for NGS as well as NGS ChIP-seq for chromatin occupancy and epigenetic studies associated with differentiation, delineation of differences between normal and diseased states. 2. Current Research Projects

GWAS in patients with agranulocytosis

GWAS in patients expressing high Hb F levels

Mapping hip dysplasia

Chromosomal targeted region enrichment using Febit Geniom Technology

Implementation of NGS-based protocols including chromatin ChIP-seq, whole transcriptome (RNA seq), whole exon sequencing, digital mRNA expression profiling, targeted cancer gene resequencing (DNA seq).

Implementation of SOLiD 3 Plus and 4 pipeline for high-performance computing for generated data flow and analysis

Implementation of genome-wide mouse SNP analysis

Initiate DNA bank of TJU patients 3. Grant Support ACTIVE Project Number: Center of Excellence on Research on Obesity (P.I.: Bonita Faulkner, M.D.) Agency: PA Department of Public Health - $863,157 Dates: 06/01/2006 - 05/31/2010 Title: Adipokines and Genotypes: Injury vs Protection in Obesity-Related Co-Morbidity Role: Co-Investigator 3 calendar The purpose of this project is to conduct research on biomarkers that protect against obesity-related diseases in order to advance treatments and to reduce racial disparities. Project Number: 2 P30 CA056036-10 (P.I.: R. Pestell, M.D.) Agency: NIH - NCI – $238,237 Dates: 06/22/95 - 05/31/13 Title: Translational research in cancer: Institutional Cancer Core Role: Director, Cancer Genomics Shared Resource 3 calendar The major goal of this project is to provide genomic-based services to KCC investigators.

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Project Number: 1 R01 CA132115-01A1 (P.I.: R. Pestell, M.D.) Agency: NIH-NCI - $207,500 Dates: 07/20/09 - 06/30/11 Title: DACH1/Eya cell-fate determination factor and mammary tumoregenesis Role: Investigator 0.6 calendar The purpose of this project is to investigate the role of DACH1 in tumors. Project Number: (P.I.: Bonita Faulkner, M.D.) Agency: NIH - $474,300 Dates: 08/17/09-07/31/14 Title: Inflammation and Injury in Obesity Hypertension in African American Adolescents Role: Co-Investigator 1.2 calendar The major goal of this project is to identify genomic polymorphisms, which associate with phenotypes of obesity and hypertension in African Americans. 4. Future Plans

Seeking CLIA certification for complex molecular, multi-analyte diagnostic tests in patients enrolled in clinical trials

K-Ras and BRAF genetic testing 5. Committees IFCC: Steering Working Committee on Nanotechnology for Molecular Applications 6. Publications

McClendon AK, Dean JL, Ertel A, Fu Z, Rivadeneira DB, Reed CA, Bourgo RJ, Witkiewicz A, Addya S, Mayhew CN, Grimes HL, Fortina P, Knudsen ES. RB and p53 Cooperate to Prevent Liver Tumorigenesis in Response to Tissue Damage. Gastroenterology. 2011 Jun 24. [Epub ahead of print]


Villa N, Bentivegna A, Ertel A, Redaelli S, Colombo C, Nacinovich R, Broggi F, Lissoni S, Bungaro S, Addya S, Fortina P, DalprÃ L. A de novo supernumerary genomic discontinuous ring chromosome 21 in a child with mild intellectual disability. Am J Med Genet A. 2011 Jun;155A(6):1425-31. Epub 2011 May 13.

Patrinos GP, Innocenti F, Cox N, Fortina P. Genetic Analysis in Translational Medicine: The 2010 GOLDEN HELIX Symposium. Hum Mutat. 2011 Jun;32(6):698-703. Epub 2011 Mar 24.

Martinez Cantarin MP, Ertel A, Deloach S, Fortina P, Scott K, Burns TL, Falkner B. Variants in genes involved in functional pathways associated with hypertension in African Americans. Clin Transl Sci. 2010 Dec;3(6):279-86.

Imai K, Kricka LJ, Fortina P. Concordance study of 3 direct-to-consumer genetic-testing services. Clin Chem. 2011 Mar;57(3):518-21. Epub 2010 Dec 15.

Del Galdo F, Wermuth PJ, Addya S, Fortina P, Jimenez SA. NFÎºB activation and stimulation of chemokine production in normal human macrophages by the gadolinium-based magnetic resonance contrast agent Omniscan: possible role in the pathogenesis of nephrogenic systemic fibrosis. Ann Rheum Dis. 2010 Nov;69(11):2024-33.

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Kricka LJ, Imai K, Fortina P. Analytical ancestry: evolution of the array in analysis. Clin Chem. 2010 Dec;56(12):1797-803. Epub 2010 Oct 13. Review.

Fortina P, Kricka LJ. Nanotechnology: improving clinical testing?. Clin Chem. 2010 Sep;56(9):1384-9.

7. Editorial Positions

1997-present Section Editor: European Journal of Human Genetics

2000-present Communicating Editor: Human Mutation

2007-present Member of Editorial Board: Human Genomics and Proteomics 8. Teaching Training

Kristine Lay: MS degree

Matthew Smith: MS degree

Michelle Lambaugh, PhD candidate Teaching in

GE637 - Advanced Human Genetics

GC550 - Foundations in Biomedical Sciences

Molecular and Cellular Basis of Medicine (MCBM) Mentoring

Dr. P. Martinez (residency in Medicine) is focused on the molecular basis of hypertension and obesity.

Dr. K. Braun (residency in Gastroenterology) is focused on the molecular basis of inflammatory bowel disease.

Dr. F. Anni (post-doctoral fellow) is focused on modifiers of disease severity in patients with sickle cell disease and beta thalassemia.

Ms. Gutman (Masters Program in Biotechnology) is focused on miRNA in cancer.

Dr. V. Alesi (post-doctoral fellow from the University of Rome School of Medicine) is involved in the use of SNP-chip DNA microarrays for detecting chromosomal imbalances

9. Memberships

American Society of Human Genetics

European Society of Human Genetics

American Association Clinical Chemistry

Association of Molecular Pathology

American Society Hematology

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Maxim V. Golovkin, Ph.D. Research Associate Professor

My research interests lie in the integrative area of biomedical research that utilizes modern plant biotechnology for production of recombinant pharmaceutical proteins. Plants have been increasingly explored as alternative bioreactors for production of subunit vaccine components and antibodies. The main advantages of plant expression systems are the low cost and greater potential for scalability when compared to traditional production systems. An additional advantage from the public’s point of view is the greater safety, because plants themselves do not contain

mammalian pathogens and can be used directly as delivery vehicles for mucosal needle-free immunization. My experimental work is primarily aimed at achieving higher yields of important therapeutic agents that display immunological activity against various diseases, including the ones considered as a threat of bio-terrorism (Rabies, SARS-CoV, Smallpox, RSV, HPV, Avian Flu, Anthrax, etc). It is done using modern constitutive and transient plant-based expression systems. Hence, all my current projects at the Biotechnology Foundation Laboratories can be summed as: "HIGH-YIELD PRODUCTION OF RECOMBINANT SUBUNIT VACCINE CANDIDATES IN PLANTA" We are using plants as a vehicle to express/produce pharmaceutical agents (antigens and antibodies) and test them to induce immune responses sufficient to protect against dangerous infections. With this approach, we are able to produce large quantities of recombinant vaccines that can be suitable for oral and other needle-free routes of immunization. Our scientific team is currently working to increase production and functional/immunogenic capabilities of a variety of such vaccine candidates (see below brief project description). Success with this and other viral antigens that we are currently working within our laboratories makes us believe that utilization of such plant-based scheme allows inexpensive production of many hard-to-express and urgently needed recombinant antigens in amounts and form suitable for different routes of immunization. Recent Publications :

Golovkin M. Plant biotechnology for production of recombinant pharmaceuticals. Hum Vaccin. 2011 Mar;7(3):303-4.

Grokhovsky SL, Il'icheva IA, Nechipurenko DY, Golovkin MV, Panchenko LA, Polozov RV, Nechipurenko YD. Sequence-specific ultrasonic cleavage of DNA. Biophys J. 2011 Jan 5;100(1):117-25.

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Linda E. Greenbaum Associate Professor

1. Description of Research Our laboratory focuses on elucidating the processes that coordinate changes in physiologic and pathologic liver growth and repair. Understanding the signaling pathways that link growth factor to cell cycle progression and repair is not only relevant to pathophysiologic states in which hepatocyte proliferation is insufficient, but also to

hyperproliferative states including hepatocellular carcinogenesis in which cell cycle checkpoints and repair pathways are frequently disrupted. Identification of signaling pathways that regulate hepatic progenitor cell self-renewal, expansion and differentiation will have wide-ranging implications for the development of therapeutics for acute liver failure, chronic cirrhotic liver disease and hepatocellular carcinoma. Current Research Projects Regulation of DNA replication in physiologic and neoplastic liver growth DNA replication is a carefully orchestrated process essential for maintaining genomic integrity and is critical for preventing chromosomal duplications or deletions associated with carcinogenesis. We found that the expression of a subset of DNA replication licensing proteins are dependent on the bZIP transcription factor C/EBPβ. We are currently investigating the mechanism responsible for C/EBPβ regulation of these DNA licensing factors in both physiologic and neoplastic models of cell growth using genetically modified mice in which C/EBPβ can be inducibly deleted in hepatocytes in vivo. Mechanisms of transcriptional control in hepatocyte proliferation by microRNAs: "Fine tuning” gene expression by small molecular weight noncoding RNA molecules including microRNAs, has been recognized as an important mechanism regulating diverse cellular processes including development, metabolism and cancer. Although several recent publications have identified strong correlations between dysregulation of specific microRNAs in the livers of patients with hepatocellular carcinoma (HCC), very little is known about the mechanism through which these microRNAs alter liver cell proliferation and lead to the development of HCC. We are using in vivo models and computational analyses to identify and then characterize the function of specific microRNAs that are important for physiologic regulation of hepatocyte growth and proliferation. Signaling pathways and the fate of hepatic progenitor cells The ability of hepatic stem cells to respond to severe liver injury depends on a finely tuned balance of cell renewal, expansion and differentiation which is controlled in part by the hedgehog, wnt and Notch signaling systems. Until now, lack of genetic tools to modulate these pathways in adult hepatic progenitors has precluded the analysis of their specific contributions to the response to liver injury. We have discovered that the forkhead transcription factor Foxl1 uniquely marks bipotential hepatic progenitor cells and have derived both constitutive and inducible Foxl1-Cre mouse strains to enable both gain- and loss-of-function studies in vivo through the targeted ablation of components of these signaling pathways. Using this approach, we are currently dissecting the signaling events that contribute to progenitor cell recruitment, differentiation and proliferation as well as par

2. Grant Support

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NIH R01 DK/CA56669 (PI-Greenbaum) 04/01/07-03/30/12 Transcriptional Control in Hepatocyte Proliferation The aims of this study are to examine the transcriptional regulation of liver growth, proliferation and metabolic homeostasis. NIH R01 DK-087958 (PI-Greenbaum) 04/01/10-03/0115 Signaling pathways and the fate of hepatic progenitor cells The aims of this study are to investigate the role of Sonic Hedgehog, Wnt and Notch signaling pathways for hepatic progenitor cell self-renewal, proliferation and differentiation Fred and Suzanne Biesecker Family Foundation (PI-Greenbaum) 01/01/10-12/31/10 The hepatic progenitor cell niche and bile duct repair The major objectives of the project are to investigate the role of Notch and Sonic Hedgehog developmental signaling pathways in hepatic progenitor cells during liver repair.

3. Future Plans Investigate the whether hepatic progenitor cells are the cell of origin in hepatocellular carcinoma that express a “stem cell signature” and identify critical signaling pathways that regulate initiation and progression of these tumors.

Identify the targets of microRNAs that are dysregulated in hepatocellular carcinomas for development of novel microRNA based therapies.

4. Committees

2009-present Graduate Group, Biochemistry and Molecular Biology 2010 KCC Pilot Grant Review Committee 2010 KCC ARRA stimulus fund pilot grant review committee 2009 NIH /NIDDK DDK-C Review Panel 2010-present NIH Review Panel: Hepatobiliary Pathophysiology Section 2008-present Vice-Chair, American Liver Foundation Grants Review Committee 2007-2010 Chair, AASLD abstract review committee, Experimental Hepatocellular Neoplasia

5. Publications

Sackett, S.D., Gao, Y., Shin, S., Esterson, Tsingalia, A., Hurtt, R., Brondell, K., Kaestner, K.H., and L.E. Greenbaum. Foxl1 promotes liver repair following cholestatic injury in mice. Laboratory Investigation, 2009, 12:1387-96. Gao, Y., Schug, J., McKenna, L.B., Kaestner, K.H., and L.E. Greenbaum. Tissue-specific Regulation of MicroRNA Genes. In Revision, Nucleic Acids Research.


Greenbaum, L. E. and R. G. Wells, The Role of Stem Cells in Liver Repair and Fibrosis, International Journal of Biochemistry and Cell Biology, Epub, 2009 Nov 13.

7. Presentations

INVITED SEMINARS 2010 Division of Gastroenterology and Hepatology, University of Southern California

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INVITED PRESENTATIONS 2009 Moderator, Stem Cells Workshop, American Association for the Study of Liver

Diseases Annual Meeting 2010 Invited Speaker, FASEB Summer Research Conference


2007- present Editorial Board, Hepatology 2007-present Consulting Editor, Journal of Clinical Investigation 2007-present Editorial Board, American Journal of Physiology

9. Teaching 2009-present Member of Thesis Committee for Jason Correnti, TJU. Mentor: Jan Hoek. 2010-present Member of Thesis Committee for Ryan Bourgo, TJU. Mentor: Erik Knudsen. 2009 “Stem Cells in Liver Fibrosis and Cancer, Division of Gastroenterology and

Hepatology

10. Memberships American Association for the Study of Liver Disease American Gastroenterological Society International Liver Cancer Association American Society for Biochemistry and Molecular Biology

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D. Craig Hooper, Ph.D. Associate Professor

1. Description of Research Entry of circulating cells and factors into the tissues of the central nervous system (CNS) is regulated by the blood-brain barrier (BBB). The central theme of the work in my laboratory is the understanding of how innate and adaptive immune mechanisms regulate BBB function. The maintenance of BBB integrity is important to protect sensitive CNS tissues from immune attack, as occurs in diseases like multiple sclerosis while functional changes in the BBB are necessary to provide immune

effectors access to infected or neoplastic brain tissues. Our studies are directed at elucidating how T cells, B cells, and antibody enter CNS tissues and act to clear the neurotrophic rabies virus. We have determined that an interferon-gamma-dependent process mediates therapeutic delivery of immune effectors into CNS tissues resulting in virus clearance and are working to elucidate the precise molecular mechanisms involved. In collaborative work we have engineered novel recombinant rabies virus vaccines that target immune effectors to CNS tissues. These are currently under development for use in the post-exposure treatment of rabies which remains a significant worldwide health problem with over 60,000 human deaths a year. In addition, in another collaboration we are working to provide mechanistic support for the establishment of an immune intervention clinical trial in glioblastoma multiforme (GBM). With a view to improving the outcome of vaccination against GBM, we are also working define the nature of the immunoregulatory processes that protect gliomas against immune intervention. 2. Current Research Projects

1. Mechanisms of immune clearance of virus from the CNS. 2. Nature of antibodies capable of infiltrating CNS tissues and alterations in blood-brain barrier

function involved. 3. Regulation of blood-brain barrier integrity during CNS immunity, inflammation, and cancer. 4. Development of improved live-attenuated rabies virus vaccines for virus clearance from CNS

tissues. 5. The contribution of radical activity to neurodegenerative processes in the absence of

inflammation. 3. Grant Support Host-pathogen competition in IFN mediated antiviral defense. NIH/NIAID UO1 AI083046, 05/01/2009-04/30/2014, PI Hooper, $253,088 direct costs, 05/01/010-04/30/2011. Passive Immunization for Neurotrophic Virus Infection. NIH/NIAID R01 AI060005, 04/01/07-03/31/10, PI Hooper, $171,675 direct costs 04/01/09-03/31/11. No cost extension. Vaccination against glioblastoma. Paparone, Thomas Stevens, and Yepremian Foundations, undetermined, P.I. David Andrews, M.D., collaboration with the work of three investigators being supported in the laboratory. 4. Future Plans To develop the methodology and reagents to clear viruses from the CNS tissues. Using rabies as a model we have developed live attenuated vaccines and monoclonal antibodies capable of clearing an otherwise lethal rabies virus infection from the CNS in mouse models. We are developing a consortium

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with three other institutions to apply for NIH funding to provide support for translational studies to move this work into human treatment. The lead vaccine for this work is in the process of being licensed to a pharmaceutical firm based in India where there were over 50,000 human deaths from rabies last year.

To exploit our findings in rabies and CNS autoimmunity to develop new modalities to deliver brain tumor-specific immune effectors into CNS tissues bearing glioblastoma multiforme. In collaboration with Drs. David Andrews and Larry Harshyne of the Department of Neurological Surgery we have developed a novel vaccine that is highly effective at preventing growth of a transplantable glioma in mice. Immunization of mice already bearing a glioma is ineffective in part due to the production of the anti-inflammatory cytokine IL10 in the tumor. We have constructed a live-attenuated rabies virus vaccine that may overcome the effects of IL10 and will assess this possibility. 5. Committees Institutional Review Board (W) Institutional Biosafety Committee Committee on Research Reapplication Enhancement Award Sub-committee Immunology and Microbial Pathogenesis PH.D. Program Core Committee Translational Research Oversight Committee Cancer Center Animal Colony Committee 6. Publications

Hooper DC, Roy A, Kean RB, Phares TW, Barkhouse DA. Therapeutic immune clearance of rabies virus from the CNS. Future Virol. 2011 Mar 1;6(3):387-397.

Li J, Faber M, Dietzschold B, Hooper DC. The role of toll-like receptors in the induction of immune responses during rabies virus infection. Adv Virus Res. 2011;79:115-26. Review.

Hooper DC, Roy A, Barkhouse DA, Li J, Kean RB. Rabies virus clearance from the central nervous system. Adv Virus Res. 2011;79:55-71. Review.

Vetting MW, Hegde SS, Wang M, Jacoby GA, Hooper DC, Blanchard JS. Structure of QnrB1, a plasmid-mediated fluoroquinolone resistance factor. J Biol Chem. 2011 Jul 15;286(28):25265-73. Epub 2011 May 19.

Truong-Bolduc QC, Bolduc GR, Okumura R, Celino B, Bevis J, Liao CH, Hooper DC. Implication of the NorB efflux pump in the adaptation of Staphylococcus aureus to growth at acid pH and in resistance to moxifloxacin. Antimicrob Agents Chemother. 2011 Jul;55(7):3214-9. Epub 2011 May 9.

Castegna A, Palmieri L, Spera I, Porcelli V, Palmieri F, Fabis-Pedrini MJ, Kean RB, Barkhouse DA, Curtis MT, Hooper DC. Oxidative stress and reduced glutamine synthetase activity in the absence of inflammation in the cortex of mice with experimental allergic encephalomyelitis. Neuroscience. 2011 Jun 30;185:97-105. Epub 2011 Apr 24.

Didier JP, Villet R, Huggler E, Lew DP, Hooper DC, Kelley WL, Vaudaux P. Impact of ciprofloxacin exposure on Staphylococcus aureus genomic alterations linked with emergence of rifampin resistance. Antimicrob Agents Chemother. 2011 May;55(5):1946-52. Epub 2011 Feb 28.

Kim HB, Park CH, Gavin M, Jacoby GA, Hooper DC. Cold shock induces qnrA expression in Shewanella algae. Antimicrob Agents Chemother. 2011 Jan;55(1):414-6. Epub 2010 Nov 15.

Hyle EP, Ferraro MJ, Silver M, Lee H, Hooper DC. Ertapenem-resistant Enterobacteriaceae: risk factors for acquisition and outcomes. Infect Control Hosp Epidemiol. 2010 Dec;31(12):1242-9. Epub 2010 Oct 28.

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7. Book Chapters and Reviews Hooper, D.C., Fabis, M.J., Roy, A. Free Radicals in Central Nervous System Inflammation. Oxidative Stress and Free Radicals in Neurology, N. Gadoth, H. Hilmar (Eds.) Springer Verlag, Berlin, Heidelberg, New York, 2010.

8. Presentations

“Active and passive immunization” Future Therapy of Human Rabies Encephalitis, Quebec City, Quebec, Canada, October 18, 2009.

“Inhibition of rabies virus replication and spread in CNS tissues by passively administered antibody”. Rabies in the Americas XIX, CDC, Quebec City, Quebec, Canada, October 19, 2009.

“Delivery of immune effectors across the blood-brain barrier”. KCC Joint Faculty Seminar, TJU, November 9, 2009.

“Delivery of therapeutics across the blood-brain barrier by immune mechanisms” Pennsylvania Biotechnology Center, Doylestown, Pennsylvania, November 12, 2009.

“Innate and adaptive immune mechanisms in the clearance of rabies virus from the CNS”. Immune Mechanisms of Virus Control (IMVC) Kickoff Meeting, Bethesda, Maryland, December 1, 2009.

“Vaccination for central nervous system immunity” Jefferson Vaccine Center, TJU, December 4, 2009.

“The production of antibody by invading B cells is required for the clearance of rabies virus from the central nervous system”. CDC Zoonotic Disease Conference Call, January 6, 2009.


Editorial Board of Clinical and Developmental Immunology

10. Teaching IMP 505 Fundamentals of Immunology – Lecturer: “T cell-mediated autoimmunity”, “Mucosal Immunity”, “Vaccinology”. NS 625 Neurovirology – Lecturer: “Immune activation in viral infection”, “Blood-brain barrier”, “Virus clearance from the CNS”, “Virus-induced inflammation”. IMP 655 Advanced Topics in Microbial Pathogenesis – Lecturer: “Borna Disease”. MI 920 – Ph.D. Thesis Research: student Darryl Barkhouse

11. Memberships SURE-PD Clinical Trial Steering Committee IMVC Steering Committee Ph.D. Committee, Rachel Knight, University of Texas Medical Branch, C.J. Peters, advisor. NIH, NIAID Review Panels: “Protection of Human Health by Immunology and Vaccines” ZAI1-QV-I (M1 & M2) March 1-3, 15-17, 2009. NIH, NCCAM Special Emphasis Panels: Basic Science ZAT PK (09, 10), October 19-20, 2009, March 8-9, 2010.

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Xuanmao Jiao, Ph.D. Instructor

Description of Research The protooncogene c-Jun encodes a major component of the AP-1 transcription factor and regulates diverse biological functions including proliferation, apoptosis and migration. Several lines of evidence suggest that c-Jun is involved in breast cancer tumorigenesis and metastasis. Our work showed that c-Jun is necessary for cell migration and invasion. In 3T3 fibroblast, c-Jun knock out reduced cell migration and invasion through reducing the secretion of stem cell factor (SCF). The reduction in SCF

correlated with altered c-Src expression, hyperactivating ROCK II signaling. We also demonstrated in c-Jun-/- cells that c-Jun regulates cellular morphogenesis, focal adhesion turnover rate, focal adhesion number and stress fiber formation. We demonstrated that c-Jun increased in mammary epithelial cell migration. Our preliminary data demonstrated high c-Jun expression correlated with expression of stem cell markers. The ErbB2 transmembrane receptor is overexpressed in approximately 30% of human tumors. Mammary gland targeted ErbB2 overexpression is sufficient for mammary tumorigenesis in vivo. We generated FloxP-c-jun/ErbB2 double transgenic mice, and derived several stable FloxP-c-jun/ErbB2 mammary tumor cell lines. FloxP-c-Jun/ErbB2/MMTV-Cre triple transgenics were generated to excise c-Jun in the mammory glands of transenic mice. Genome wide microarray expression studies of laser capture microdissected mammary epithelium demonstrated c-Jun expression correlated with a stem cell expression signature in vivo. c-Jun was deleted in vivo by Cre recombinase. In the cell lines our data showed ErbB2 increased cell motility and invasiveness and c-Jun knock out abrogated breast tumor invasiveness. c-Jun knock out also decreased mammosphere formation in ErbB2 tumor cells. Our mechanistic studies demonstrate c-Jun induces the production of a secreted factor that promotes cancer stem cell expansion and cellular invasiveness. These studies will identify this secreted factor and determine whether inactivation of this factor blocks breast cancer metastasis. Future plans More and more evidence showed that there is tumor stem cell and tumor stem cell played very important role in the resistance of tumor therapy. Our future plan is to study the role of c-Jun, cyclin D1 and Dach1 in stem cell expansion and differentiation. Current Research Projects The role of c-Jun in Breast cancer tumor metastasis and stem cell expansion Publications

Janowski E, Jiao X, Katiyar S, Lisanti MP, Liu M, Pestell RG, Morad M. c-Jun is required for TGF-Î²-mediated cellular migration via nuclear CaÂ²â•º signaling. Int J Biochem Cell Biol. 2011 Aug;43(8):1104-13. Epub 2011 Apr 5.

Meng H, Tian L, Zhou J, Li Z, Jiao X, Li WW, Plomann M, Xu Z, Lisanti MP, Wang C, Pestell RG. PACSIN 2 represses cellular migration through direct association with cyclin D1 but not its alternate splice form cyclin D1b. Cell Cycle. 2011 Jan 1;10(1):73-81. Epub 2011 Jan 1.


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Li Z, Jiao X, Wang C, Shirley LA, Elsaleh H, Dahl O, Wang M, Soutoglou E, Knudsen ES, Pestell RG. Alternative cyclin D1 splice forms differentially regulate the DNA damage response. Cancer Res. 2010 Nov 1;70(21):8802-11. Epub 2010 Oct 12.


Committees Bioimaging Facility Oversight Committee at Kimmel Cancer Center Memberships American Society of Cell Biology

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Xiaoming Ju, M.D. Instructor

1. Description of Research Prostate cancer oncogenesis. I have developed new cancer cell lines through transduction of prostate epithelial cells using oncogenic Ha-Ras, c-Myc, v-Src and ErbB2 (NeuT). My studies are focused on the effects of distinct oncogene on the angiogenesis, stem cell population in prostate cancers. I am also working on the cyclinD1 & AR project, The aim of our research is to determine new mechanisms regulating

androgen receptor (AR) function in prostate cancer cellular growth. We want to determine in vivo significance of AR regulation by cyclin D1 / AKT1. We also try to determine functional significance of these genes in prostate cellular growth in vivo. Breast Cancer oncogenesis. My research is focused on the role of AKT gene plays in the proliferation, invasion, and metastasis of breast cancer in vitro and in vivo. 2. Current Research Projects

Genetic characteristics of distinct oncogenes transformed PEC cell lines and the influence on the angiogenesis and stem cell population.

The relationship of cyclinD1 and Androgen receptor (AR) function in prostate cancer cellular growth.

Dose dependent AKT expression regulates invasion and metastasis of breast cancer cell. 3. Grant Support NIH, R01 CA86072-07 (Pestell) (4/1/09 – 3/31/14) $250,000/yr Androgen Receptor Function in Prostate Cancer. 4. Future Plans Keep working on my projects, hope to get more publications in next school year and make progress in my research and career 5. Publications

Katiyar S, Casimiro MC, Dettin L, Ju X, Wagner EF, Tanaka H, Pestell RG. C-jun inhibits mammary apoptosis in vivo. Mol Biol Cell. 2010 Dec;21(23):4264-74. Epub 2010 Oct 6.


6. Memberships American Associate of Cancer Research. Active member.

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Erik Knudsen, Ph.D. Professor

1. Research Foci Research is focused on the retinoblastoma tumor suppressor (RB). This tumor suppressor is lost or functionally inactivated in the majority of human cancers. The Knudsen laboratory takes a multi-disciplinary approach to understanding how RB functions to inhibit tumorigenesis and to devise new means to effectively target the RB-pathway in the treatment of cancer.

2. Current and Ongoing Projects Influence of RB on DNA replication machinery and cell cycle control: The laboratory has identified three distinct means through which RB inhibits DNA replication and believe that relief of this multi-fold regulation is one of the reasons why RB loss is targeted at such high frequency in human cancers. Current investigation has revealed that other tumor suppressors can target DNA replication control, but through mechanisms that are distinct from that of RB. In model systems, loss of RB can either enhance proliferation or lead to genomic instability. Currently, we are defining how RB dysfunction leads to these distinct outcomes and are modeling their relevance to human cancers. Role of RB in liver tumorigenesis and other environmentally-induced cancers: Liver cancer is a major health concern. Currently, this disease is the 3rd leading cause of cancer deaths worldwide with over 400,000 new diagnoses each year. One of the key genetic lesions found in liver cancer is inactivation of RB. However, the role of RB loss in tumor etiology and progression remains largely undefined. To determine the mechanism(s) by which RB prevents tumor formation in the liver, a number of mouse model of liver specific RB deletion were interrogated. These studies revealed a novel mechanism of RB function, indicating that RB action in this tissue is distinct from its ability to prevent unchecked cellular proliferation. Rather, our data support the hypothesis that RB loss cooperates with hepatic carcinogens to induce genomic instability and promote liver tumorigenesis. Liver cancer is just one of many human cancers that has a strong environmental component. Therefore, in addition to specific studies dissecting the action of RB loss in the liver, we have also begun to model bladder cancer, which is induced by carcinogens from cigarettes and other toxic materials. Action of RB in modifying response to therapy: Given the high frequency of RB loss in human cancers we have postulated that RB-status could be an important determinant of therapeutic outcomes. Approaches currently used to treat breast cancer include hormonal, cytotoxic, and targeted therapeutic agents. Interestingly, diverse therapeutic agents function through common down-stream pathways that effect cellular proliferation--particularly, they all impinge upon the cell cycle machinery. One component of cell cycle control, which is compromised in breast cancer at high frequency, is the RB-pathway. We have found that RB is a critical determinant of hormonal therapies, such that RB-deficient tumors fail to effectively respond to tamoxifen. Additionally, we have found that deregulation of the RB-pathway is associated with early relapse in breast cancer patients treated with tamoxifen. In contrast, loss of RB enhances sensitivity to specific cytotoxic agents. Ongoing studies are dissecting additional agents utilized in the treatment of breast cancer and other tumor types (e.g. lung cancer), wherein RB status may be equally important in modifying therapeutic response.

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p16ink4a and Cyclin D1 aberrations in human cancer: RB functions in a pathway which is controlled by the functional interplay between upstream regulators: particularly the tumor suppressor p16ink4a and proto-oncogene cyclin D1. Interestingly, overproduction of cyclin D1 or loss of p16ink4a have distinct effects on cell cycle control and suggest that intrinsic differences between components of the RB-pathway impact tumor behavior and therapeutic response. In this context we are exploring the function of tumor associated variations in p16ink4a and cyclin D1 (e.g. cyclin D1b) in relation to tumor development, as markers of tumor behavior and modifiers of therapy. 3. Grant Support: ACTIVE: NIH 5P30 CA056036-10 (Pestell) $257,869 ($257,869/yr) 06/22/95 – 05/31/13 Translational Research in Cancer Senior Leadership (Deputy Director Basic Science) NIH R01CA137494 (E Knudsen/Pestell) $250,000 direct/year 07/01/10 - 06/30/15 Cyclin D1 variants in breast cancer NIH R01 CA129134 (E Knudsen) $250,000 direct/year 07/01/10 - 06/30/2015 Action of RB Pathway in Breast Cancer Therapy PA Tobacco Funds (E Knudsen) $200,000 direct/year 12/01/07 - 11/30/11 RB pathway function NIH R01 CA127387 (E Knudsen) $200,000 direct/year 01/01/08 - 12/31/12 RB tumor suppressor: action in liver tumorigenesis NIH R01 CA104213 (E Knudsen) $164,000 direct/year 06/01/04 - 05/31/10 BRG1/BRM: role in RB tumor suppressor signaling NIH R01 CA106471 (E Knudsen) $164,000 direct/year 08/01/04 - 7/31/10 RB mediated replication control Pfizer $195,000 total 01/01/10 - 06/01/11 Therapeutic Targeting of the RB-pathway 4. Future Plans

To develop robust markers of RB function that can be used to inform therapeutic decisions.

To identify underlying mechanisms of RB dysfunction in breast cancer and determinants of therapeutic response.

To determine how cyclin D1 variants function in the context of breast and liver cancer.

To define novel therapeutic interventions for the treatment of diverse cancers based on the RB-pathway

5. Publications (July 1, 2009-present):

McClendon AK, Dean JL, Ertel A, Fu Z, Rivadeneira DB, Reed CA, Bourgo RJ, Witkiewicz A, Addya S, Mayhew CN, Grimes HL, Fortina P, Knudsen ES. RB and p53 Cooperate to Prevent Liver Tumorigenesis in Response to Tissue Damage. Gastroenterology. 2011 Jun 24. [Epub ahead of print]

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Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, Wang C, Flomenberg N, Knudsen ES, Howell A, Pestell RG, Sotgia F, Lisanti MP. Ketones and lactate increase cancer cell stemness driving recurrence, metastasis, and poor clinical outcome in breast cancer: Achieving personalized medicine via Metabolo-Genomics. Cell Cycle. 2011 Apr 15;10(8):1271-86.

Witkiewicz AK, Knudsen ES. RB pathway and therapeutic sensitivity: new insights in breast cancer and Tamoxifen therapy. Cell Cycle. 2011 May 15;10(10):1525. Epub 2011 May 15.


Bourgo RJ, Ehmer U, Sage J, Knudsen ES. RB deletion disrupts coordination between DNA replication licensing and mitotic entry in vivo. Mol Biol Cell. 2011 Apr;22(7):931-9. Epub 2011 Feb 2.


Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C, Morrissey C, Zhang X, Comstock CE, Witkiewicz AK, Gomella L, Knudsen ES, Nelson PS, Knudsen KE. The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest. 2010 Dec 1;120(12):4478-92.

Ertel A, Dean JL, Rui H, Liu C, Witkiewicz AK, Knudsen KE, Knudsen ES. RB-pathway disruption in breast cancer: differential association with disease subtypes, disease-specific prognosis and therapeutic response. Cell Cycle. 2010 Oct 15;9(20):4153-63. Epub 2010 Oct 27.

Li Z, Jiao X, Wang C, Shirley LA, Elsaleh H, Dahl O, Wang M, Soutoglou E, Knudsen ES, Pestell RG. Alternative cyclin D1 splice forms differentially regulate the DNA damage response. Cancer Res. 2010 Nov 1;70(21):8802-11. Epub 2010 Oct 12.

Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C, Whitaker-Menezes D, Daumer KM, Lin Z, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG, Knudsen ES, Sotgia F, Lisanti MP. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle. 2010 Aug 15;9(16):3256-76. Epub 2010 Aug 28.

6. REVIEWS AND BOOK CHAPTERS:

Knudsen, E.S. (2009). Replication factors controlling G(1): A checkpoint for pre-replication complex assembly. Cell Cycle. 1;8(1).

McClendon, A.K., Dean, J., Knudsen, E.S. (2010). Complex role for CDK/cyclin in the control of DNA replication licensing. In press.

7. INVITED SEMINARS:

2007 Invited Speaker, Biomedical Sciences, Florida State University

2007 Invited Speaker, University of Southern California, Norris Cancer Center

2007 Invited Speaker, Pharmacology, University of Pittsburgh

2007 Invited Speaker, University of Alabama Birmingham, Cancer/Pathology

2008 Invited Speaker, Temple University, Fels Institute for Cancer Research

2008 Invited Speaker, University of Toronto, Molecular Medicine

2008 Invited Speaker, University of Ottawa

2008 Invited Speaker, Drexel University, Biochemistry

2009 Invited Speaker, Lankenau Institute for Medical Research

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2009 Invited Speaker, A/I Dupont Nemours, Pediatric Research Unit

2009 Invited Speaker, University of California, Davis

2009 Invited Speaker, New York University, Pharmacology

2010 Invited Speaker, University of Pennsylvania, Gastroenterology

2010 Invited Speaker, Columbia University, Department of Oncology

2010 Invited Speaker, Mount Sinai University, Hematology Oncology INVITED PRESENTATIONS:

2009 Invited Speaker, AACR Annual meeting

2009 Invited Speaker, Cancer Center Retreat, Michigan State University

2009 Invited Speaker, Annual Retinoblastoma Meeting

2010 Invited Speaker, Golden Helix International Genomics, Athens Greece 8. COMMITTEES: KCC Executive Committee KCC Education Committee KCC Basic Science Advisory Committee KCC Training Committee KCC Program Advisory Committee, Chair Thomas Jefferson University, Appointments/Promotions Committee 9. Editorial Activities:

2005-present Editorial Board, Cancer Molecules

2008-present Editorial Board, Am. J. Pathology

2009-present Editorial Board, Genes and Cancer

2009-present Editorial Board, Mutation Research Reviews

2010-present Editorial Board, Cancer Research

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Karen E. Knudsen Associate Professor

Department of Cancer Biology and Department of Urology Research Foci: Prostate cancer is the most commonly diagnosed malignancy and second leading cause of cancer death in U.S. men. Early prostate cancers require androgen to survive and proliferate; this dependence is exploited in treatment for disseminated disease, wherein androgen ablation in the first line of therapeutic intervention. Although these regimens are initially effective, tumors ultimately recur due to reactivation of androgen receptor (AR) signaling, causing treatment failure and patient morbidity. Despite the importance of understanding androgen action in the prostate, little is understood about

the mechanisms underlying androgen dependence, and the means by which the androgen requirement is bypassed in relapsed tumors. My lab is dedicated to delineating the mechanisms that govern these events, and in the design of new points of therapeutic intervention. Current and Ongoing Projects: We currently have four main projects in the lab: 1. Regulation of AR dependent gene expression and cellular proliferation by cell cycle crosstalk in prostate cancer. Cyclin D1 is an integral component of the cell cycle machinery that is induced by androgen in prostatic adenocarcinoma cells. However, we and others have shown that Cyclin D1 has a second role in the regulation of androgen dependent proliferation, manifested through its ability to modulate AR activity. We have shown that Cyclin D1 binds the AR directly and through interaction with the N-terminus inhibits AR transactivation potential. Interaction between AR and Cyclin D1 has been shown with endogenous proteins. The repressor function of Cyclin D1 occurs independently of its role in the cell cycle, is dominant to the effects of known AR co-activators, and attenuates the rate of androgen dependent proliferation. Our data put forth the hypothesis that Cyclin D1 is a critical mediator of AR activity, that could be exploited to inhibit androgen-dependent proliferation. In this line of investigation, we will address the mechanism of Cyclin D1 co-repressor activity and evaluate its efficacy in vivo as an inhibitor of androgen-dependent proliferation. 2. Impact of SWI/SNF chromatin remodeling factors on AR function and prostate tumorigenesis. We and others have shown that AR requires the action of an ATP dependent chromatin-remodeling complex, SWI/SNF, to induce gene transcription. SWI/SNF exists in vivo as a series of biochemically diverse complexes, and the variant composition of SWI/SNF complex is thought to underlie its specificity in transcriptional control. We have recently determined that BAF57, a non-essential SWI/SNF subunit, is critical for AR modulation. We show that BAF57 interacts directly with AR, is recruited to AR target promoters in the prostate upon androgen stimulation, and is required for AR transactivation potential. This effect of BAF57 also governs AR co-activator function, as BAF57 was required for co-activator mediated AR enhancement and cooperated with selected co-activators to augment AR function. Lastly, we demonstrate that abrogation of BAF57 function specifically attenuates AR dependent (but not ER dependent) cellular proliferation. Collectively, these studies implicate BAF57 as a critical regulator of AR and CaP proliferation, thus identifying BAF57 as a target for potential therapeutic intervention. Our data support the hypothesis that BAF57 is a critical mediator of AR activity, acting through discrete mechanisms to control androgen dependent proliferation. In this line of investigation, we will uncover

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the mechanisms by which BAF57 regulates AR, examine the specificity of this event under conditions related to prostate cancer progression, and evaluate the impact of BAF57 ablation in vivo on AR-dependent signaling and proliferation. 3. Impact of cell cycle deregulation on therapeutic efficacy: Our data predict that the G1-S promoting action of AR can be manipulated to maximize the cytotoxic action of S-phase or G2/M dependent therapeutics. This concept will be rigorously challenged herein using both in vitro and in vivo analyses. In addition, a novel strategy will be used manipulate CDK activity for enhancing the anti-tumor action of taxanes. Based on mechanisms of action, the proposed studies take advantage of AR-dependent cell cycle regulation in PCa cells to reveal new strategies to effectively combat androgen dependent tumors. Through these studies, it is our belief that novel approaches to improve disease management will be revealed, and it is hoped that the data generated can be used to rapidly translate into a clinical trial to improve PCa management. 4. Role of endocrine disrupting compounds (EDCs) in circumventing the androgen requirement. We demonstrated that BPA inappropriately activates a specific subset of tumor-derived AR mutants, and through this mechanism stimulates prostate cancer cell proliferation under conditions of androgen depletion. The mitogenic action of BPA was sufficient in a xenograft model of prostate cancer to shorten the time to recurrence and enhance tumor growth after therapeutic intervention. These data were the first to examine the impact of endocrine-disrupting compounds (EDCs) on prostate cancer management, revealed the focal point of BPA activity, and have important clinical implications. In a recent comprehensive screen, we determined that multiple EDCs impinge on specific AR mutants to facilitate cellular proliferation. Combined, these findings support the hypothesis that specific environmental agents can contribute to therapeutic bypass in prostate cancer, and that EDC action is facilitated through secondary events known to occur during tumor progression. This section of the lab will to determine the mechanism, specificity, and consequence of EDC activity in prostate cancer: Grant Support: R01 CA116777 (PI Karen E. Knudsen) 06/01/06-07/31/11 “Role of BAF57 in AR control and prostate cancer growth”: The goal of this project is to examine the mechanisms by which BAF57 induces AR function and regulates AR-dependent proliferation. R01 ES016675-06 (PI Karen E. Knudsen) 04/01/02-08/31/12 “Endocrine Disruption and Prostate Cancer Therapy”: The goal of this project is to determine the mechanisms by which xenoestrogens influence androgen receptor function and prostate cancer therapy. R01 CA099996 (PI: Karen Knudsen) 06/01/09-05/31/2014 Cyclin D1: Mechanism and consequence of AR inhibition”: The goal of this project is to examine cross talk between the androgen receptor and the cell cycle machinery, with a specific emphasis on cyclin D1a. The specific aims were designed to delineate the mechanism and specificity of cyclin D1a activity on hormone function. Prostate Cancer Foundation Creativity Award (joint PIs: Adam Dicker & Karen Knudsen) 03/01/09-03/01/10

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Self-seeding and radiation therapy: a new strategy against metastatic prostate cancer. This award will test the novel hypothesis that survival of widespread metastases are dependent on the local tumor environment. Future Plans:

To develop metrics of therapeutic response in prostate cancer.

To identify new points of therapeutic intervention through interrogation of the androgen receptor pathway

To determine the impact of cell cycle control on prostate cancer progression. Publications:



Olsen A, Christensen J, Knudsen KE, Johnsen NF, Overvad K, Tjønneland A. Prediagnostic plasma enterolactone levels and mortality among women with breast cancer. Breast Cancer Res Treat. 2011 Aug;128(3):883-9. Epub 2011 Feb 22.

Knudsen KE. A tale of three PKCs: epsilon emerges as a driver of pre-neoplastic phenotypes. Cell Cycle. 2011 Feb 1;10(3):379. Epub 2011 Feb 1. No abstract available.


Jensen RB, Brokner C, Knudsen KE, Tauson AH. A comparative study of the apparent total tract digestibility of carbohydrates in Icelandic and Danish warmblood horses fed two different haylages and a concentrate consisting of sugar beet pulp and black oats. Arch Anim Nutr. 2010 Oct;64(5):343-56.

Sharma A, Yeow WS, Ertel A, Coleman I, Clegg N, Thangavel C, Morrissey C, Zhang X, Comstock CE, Witkiewicz AK, Gomella L, Knudsen ES, Nelson PS, Knudsen KE. The retinoblastoma tumor suppressor controls androgen signaling and human prostate cancer progression. J Clin Invest. 2010 Dec 1;120(12):4478-92. doi: 10.1172/JCI44239. Epub 2010 Nov 22.


Nilsson AC, Östman EM, Knudsen KE, Holst JJ, Björck IM. A cereal-based evening meal rich in indigestible carbohydrates increases plasma butyrate the next morning. J Nutr. 2010 Nov;140(11):1932-6. Epub 2010 Sep 1.

INVITED SEMINARS: 2009 Mount Sinai School of Medicine, Oncological Sciences 2009 University of Toledo, Biochemistry and Oncological Sciences 2009 Mayo Clinic College of Medicine, Urology, Biochemistry and Molecular Biology 2009 University of Maryland, Pathology 2009 University of Delaware, Cancer Center

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2009 University of Kansas Medical Center, Cancer Center INVITED PRESENTATIONS: 2009 Endocrine Society Meeting (to accept the Richard E. Weitzman Award) 2009 Gordon Conference, Hormone Action 2009 Society for Basic Urologic Research 2010 Keystone Nuclear Receptor Symposium (*speaker and co-organizer) TEACHING: 2009 Lead Instructor, Genetics Program Journal Club/Data Analyses Course (200802.GE.720.01) COMMITTEES: 2007-present Member, Kimmel Cancer Center 2007-present Member, EMHAC Program 2007-present Director, Greater Philadelphia Prostate Cancer Working Group 2008-present Member, Genetics PhD Program Graduate Committee Editorial Activities: 2006-present Editorial Board, Molecular Cancer Therapeutics 2007-present Associate Editor, Endocrine Related Cancer 2007-present Senior Editor, Cancer Research 2008-present Editorial Board, The Prostate 2008-present Editorial Board, American Journal of Pathology Memberships and Positions in Professional and Academic Societies: National Societies American Association for Cancer Research (Active Member 2000-present) Endocrine Society (Active Member, 2004-present) Society for Basic Urologic Research (Active Member, 2005-present) National Scientific Committees: NIH Cancer & Molecular Pathobiology study section, (Ad hoc 2004-05; Member 2006-present) AACR Annual Meeting Committee, Exhibits (Member, 2009-present) Scientific Advisory Board, Delaware INBRE program International Scientific Committees Australian Prostate Cancer Research Centre, University of Adelaide (2008-present) Jamaican Disaspora Committee on Cancer Prevention (2008-present)

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Hilary Koprowski, M.D. Professor

1. Description of Research Production of safe, effective and inexpensive vaccines preferably for needle-free routes of immunization 2. Current Research Projects

a. Microbicides For Prevention of HIV Infection b. Needle-Free Vaccine Against Cervical Cancer c. Antibodies for the Treatment of Cancer and Development of

Cancer Vaccine d. Needle-Free Smallpox Vaccine e. Poliomyelitis Vaccine – New Generation f. Improved DPT Vaccine g. Commercial Fish Vaccine h. Multiple Sclerosis

3. Grant Support U.S. Department of Agriculture $97,561 Development of Chimeric Plant Viruses to Express Full Length Therapeutic Proteins in Plants. Main goal: To develop and test new strategies and plant expression systems for the production of vaccines and other biomedical products for the prevention and treatment of animal diseases. Commonwealth of Pennsylvania $500,000 Department OF Health Production of Plant-based Vaccines and other Biomedical Against AIDS and Other Diseases. Main goal: Production of human and animal vaccines and other biopharmaceuticals in plants. PENDING: Title: Tobacco Biomass for Biofuel Production, Both Ethanol and Biodiesel Agency: Department of Environmental Production, Commonwealth of Pennsylvania Principal Investigator: Hilary Koprowski Main goal: To develop a technological basis for the subsequent production of ethanol and diesel biofuels using green tobacco biomass. 4. Future Plans We will perfect a vaccine against uterine cancer through plant biotechnology using vaginal suppositories. Complete the development of poliomyelitis vaccine based on immunization of the world population with plant-derived virus-like particles instead of living virus. Improvement in the extraction procedure of fuel oil from biomass for commercial use. 5. Committees Committee on Committees

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6. Publications (July 1, 2009 to June 30, 2010) Andrianov, Vyacheslav, Nikolai Borysyuk, Natalia Progrebnyak, Anita Brinker, Joseph Dixon, Sergei Spitsin, John Flynn, Paulina Matyszczuk, Karolina Andryszak, Marilyn Laurelli, Maxim Golovkin and Hilary Koprowski. 2009. Tobacco as a production platform for biofuel: overexpression of Arabidopsis DGAT and LEC2 genes increases accumulation and shifts the composition of lipids in green biomass. Plant Biotechnology Journal 8: 1-11. 7. Book Chapters and Reviews 8. Presentations 9/28/09 Lecture by Dr. Koprowski in Atlanta, GA at the Centers for Disease Control (CDC) World Rabies Day. Title: “Rabies.” 10/19/09: Lecture by Dr. Koprowski in Quebec City, Canada at the “Rabies in the Americas Meeting.” Title: “Experience with Rabies over the Past 60 Years.” 9. Editorial Positions

i. Springer Verlag’s “Current Topics in Microbiology & Immunology” ii. “DNA and Cell Biology”

10. Memberships American Academy of Arts and Sciences National Academy of Sciences Foreign Member, Yugoslav Academy of Arts and Sciences Foreign Member, Polish Academy of Sciences Foreign Member, Russian Academy of Medical Sciences Fellow, The Polish Institute of Arts and Sciences of America, Inc. Foreign Member, Finnish Society of Sciences and Letters, Section of Biosciences Fellow, Royal Society of Medicine, London England College of Physicians of Philadelphia New York Academy of Medicine New York Academy of Sciences (President 1959) American Association for the Advancement of Sciences American Association for Cancer Research American Association of Anatomists American Federation for Medical Research American Medical Association American Society for Cell Biology American Society for Microbiology American Society for Neurochemistry American Society for Virology

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Lucia R. Languino Professor

1. Description of Research Dr. Languino investigates the role of cell adhesion receptors in phenotypic changes of prostate cancer cells. A strong research focus is being devoted to the study of the cross-talk between cell adhesion molecules, extracellular matrix proteins and growth factor receptors in vitro and in vivo systems and how this cross-talk affects intracellular signal transduction, cell survival, cell migration and cell division. Dr. Languino's research interests also focus on the cellular and molecular characterization of the metastatic process of prostate cancer with particular emphasis on the signals directing distant

localization of prostate cancer cells. 2. Grant Support R01CA89720 (Languino) $261,630 03/01/2001 – 04/30/2015 Integrin Signaling Pathways In Prostate Cancer R01CA109874 (Languino) $260,730 09/01/2004 - 02/29/2016 Beta1 Integrins And Igf-L Receptor In Prostate Cancer P01CA140043 (Languino) $213,470 07/01/2011 – 06/30/2012 Integrin Regulation Of Prostate Cancer Progression 3. Publications (2010-2011)

Sayeed A, Alam N, Trerotola M, Languino LR. Insulin-like growth factor 1 stimulation of androgen receptor activity requires β(1A) integrins. J Cell Physiol. 2011 Apr 4. doi: 10.1002/jcp.22784. [Epub ahead of print]

Kang BH, Tavecchio M, Goel HL, Hsieh CC, Garlick DS, Raskett CM, Lian JB, Stein GS, Languino LR, Altieri DC. Targeted inhibition of mitochondrial Hsp90 suppresses localised and metastatic prostate cancer growth in a genetic mouse model of disease. Br J Cancer. 2011 Feb 15;104(4):629-34. Epub 2011 Feb 1.

Kang BH, Siegelin MD, Plescia J, Raskett CM, Garlick DS, Dohi T, Lian JB, Stein GS, Languino LR, Altieri DC. Preclinical characterization of mitochondria-targeted small molecule hsp90 inhibitors, gamitrinibs, in advanced prostate cancer. Clin Cancer Res. 2010 Oct 1;16(19):4779-88. Epub 2010 Sep 28.

Lee WH, Hung MC, Iczkowski KA, Languino LR, Dubinett SM, Wang D. Editorial Board 2010 American Journal of Translational Research (ISSN 1943-8141): www.ajtr.org Publisher: e-Century Publishing Corporation (www.e-Century.org). Am J Transl Res. 2010 Jul 30;2(4):458-62.

Goel HL, Underwood JM, Nickerson JA, Hsieh CC, Languino LR. Beta1 integrins mediate cell proliferation in three-dimensional cultures by regulating expression of the sonic hedgehog effector protein, GLI1. J Cell Physiol. 2010 Jul;224(1):210-7.

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Zhiping Li Assistant Professor

1. Description of Research Cyclin D1 is best known as the regulatory subunit of a dimeric holoenzyme including the cell cycle-dependent kinase CDK4, which phosphorylates and inactivates the retinoblastoma protein Rb to promote progression through the G1-S phase of the cell cycle. In addition to regulating the cell cycle, cyclin D1 regulates angiogenesis, lipogenesis, and mitochondrial function. Overexpression of the cyclin D1 has been reported in a variety of human

cancers including breast, colon, prostate, and hematopoietic malignancies. In invasive breast cancers, cyclin D1 is overexpressed in up to 50% of cases. The cyclin D1 gene consists of 5 distinct exons. Human cyclin D1 is expressed as two isoforms derived by alternate RNA splicing. The canonical isoform is termed as cyclin D1a. The alternatively spliced isoform is termed as cyclin D1b, which differ for the inclusion of intron 4 in the D1b mRNA. In cells, cyclin D1b has an increased transforming capacity. Cellular migration is essential for developmental morphogenesis, tissue repair, and tumor metastasis. My previous studies in Dr. Richard G. Pestell’s lab reveal that cyclin D1 acts to promote cellular migration by inhibiting Rho/ROCK signaling and expression of thrombospondin-1 (TSP-1), an extracellular matrix protein that regulates cell migration in many settings including cancer (Molecular and Cellular Biology. 2006; 26(11): 4240-56). It has been shown that p27KIP1 has a pro-migratory function through inhibiting RhoA activity. My previous study also indicates that cyclin D1 promotes cellular migration via up-regulating p27KIP1 abundance and physical interaction with p27KIP1 (Cancer Research. 2006; 66(20): 9986-94). Alternate cyclin D1 mRNA splicing modulates p27KIP1 binding and cell migration (Journal of Biological Chemistry 2008; 283(11): 7007-15).

2. Current Research Projects

Currently I am studying the role of cyclin D1 in DNA damage response and its implication in colon cancer adjuvant chemotherapy.

3. Future Plans

(1). The Role of Cyclin D1 in Breast Cancer Angiogenesis (2). The Role of Cyclin D1 in DNA Damage Response

4. Publications (2009-) Velasco-Velázquez MA, Li Z, Casimiro M, Loro E, Homsi N, Pestell RG. Examining the role of cyclin D1 in breast cancer. Future Oncol. 2011 Jun;7(6):753-65. Meng H, Tian L, Zhou J, Li Z, Jiao X, Li WW, Plomann M, Xu Z, Lisanti MP, Wang C, Pestell RG. PACSIN 2 represses cellular migration through direct association with cyclin D1 but not its alternate splice form cyclin D1b. Cell Cycle. 2011 Jan 1;10(1):73-81. Epub 2011 Jan 1. Li Z, Jiao X, Wang C, Shirley LA, Elsaleh H, Dahl O, Wang M, Soutoglou E, Knudsen ES, Pestell RG. Alternative cyclin D1 splice forms differentially regulate the DNA damage response. Cancer Res. 2010 Nov 1;70(21):8802-11. Epub 2010 Oct 12.

5. Teaching

I technically help junior faculty, postdoctoral fellows or students in their experiments.

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Jack W. London, Ph.D. Research Professor

1. Description of Research Biomedical informatics, with emphasis on clinical research and pathology informatics.

2. Current Research Projects Development of a research data warehouse which combines phenotype and “omic” data. Study of the work flow architecture of the cancer clinical trial development and conduct. Extension of tools for biospecimen data management and sharing. 3. Grant Support NCI caBIG® funding (3 contracts). Delaware Health Science Alliance (DHSA) funding for research data warehouse development. 4. Future Plans Expand pilot research data warehouse to a federated network of research resources for DVICTS. 5. Committees TJU Information Technology Security Committee TJU Technical Architecture Directions Group University I.T. Council 6. Publications (most recent) London J.W., Smalley K.S., Conner K., and Smith J.B. The Automation of Clinical Trial Serious Adverse Event Reporting Workflow. Clinical Trials 6:446-454. (2009). 7. Memberships American Medical Informatics Association Association for Computing Machinery

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Amy K. McClendon, Ph.D. Research Instructor

1. Publications McClendon AK, Dean JL, Ertel A, Fu Z, Rivadeneira DB, Reed CA, Bourgo RJ, Witkiewicz A, Addya S, Mayhew CN, Grimes HL, Fortina P, Knudsen ES. RB and p53 Cooperate to Prevent Liver Tumorigenesis in Response to Tissue Damage.

Gastroenterology. 2011 Jun 24. [Epub ahead of print] Dean JL, Thangavel C, McClendon AK, Reed CA, Knudsen ES. Therapeutic CDK4/6 inhibition in breast cancer: key mechanisms of response and failure. Oncogene. 2010 Jul 15;29(28):4018-32. Epub 2010 May 17.

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Steven B. McMahon Ph.D. Associate Professor of Cancer Biology


Function of the MYC oncogene. Genetic alterations targeting the myc oncogene are the most common transforming events in human cancer. These alterations cause overexpression of the transcription factor MYC. A thorough understanding of the MYC transcription network is critical to progress against cancer. Despite intensive study, the essential genes lying downstream of MYC remain poorly understood. Of the 629 reported MYC target genes, only 6 have documented roles in MYC-mediated transformation. An expression-profiling screen that utilized a discrete

mutant of MYC was used to selectively identify those targets relevant to transformation. This screen identified 40 novel MYC targets and studies have begun to validate their importance in MYC-driven tumorigenesis. For example, shRNA-mediated depletion of the novel target MTA1 blocks the increased invasiveness of tumor cells caused by MYC. MTA1 reportedly controls the epithelial-to-mesenchymal transition; however its link to MYC was previously unknown. Additional targets from the screen (BAG-1, POLRMT and CD30), were characterized at the molecular level and are now being characterized to determine the biological function they contribute during MYC-mediated transformation. The aim of this study is to understand the biological roles played by MTA1, BAG-1, POLRMT and CD30 in MYC-driven tumors. Together, these studies are likely to identify new cellular functions for MYC, including regulating invasiveness, blocking the anti-tumor immune response and inhibiting the apoptotic stimuli generally associated with oncogene overexpression. Using well-defined systems in which human cells can be transformed by the MYC oncoprotein in vitro, each of the targets identified will be dissected in order to understand the precise advantage they provide to MYC-driven tumor cells.

Post-translational regulation of the p53 tumor suppressor. The p53 tumor suppressor pathway is inactivated in most forms of human cancer. In normal cells, p53 is maintained at low levels by ubiquitylation and subsequent proteosome-mediated degradation. In addition to ubiquitylation, p53 is regulated by other forms of post-translational modification, including phosphorylation, acetylation and methylation. These modifications regulate a variety of p53 functions, including protein half-life, DNA binding capacity and cofactor interaction. The elimination of p53 function is critical during human carcinogenesis because the normal role of p53 is to induce either cell cycle arrest or apoptosis when a cell sustains genetic damage. As the central regulator of apoptotic cell death, the p53 pathway is of critical importance for chemotherapeutic strategies that induce genotoxic damage. Understanding the key events in the p53/apoptosis pathway is therefore of broad clinical significance.

We recently demonstrated that p53 is acetylated at a unique site, K120, within the DNA binding domain, by the MYST family acetyltransferases hMOF and TIP60. Acetylation at K120 occurs rapidly after DNA damage and several lines of evidence confirm that it is an essential event during p53-dependent apoptosis. We have further shown that the acetyl-K120 form of p53 is enriched at pro-apoptotic target genes, but not cell cycle arrest targets like p21. In addition, mutation of the acetylation site to arginine (K120R) inhibits apoptosis, without blocking cell cycle arrest. Our evidence also suggests that the acetyl-K120 form of p53 has functions outside the nucleus, perhaps via the regulation of BCL2 family interactions at the mitochondrial outer membrane. Remarkably, the inactivation of p53 by K120R mutation has been reported in a small number of human tumors, and both the enzymes that catalyze K120 acetylation (i.e. hMOF and TIP60) are lost in human tumors as well. These observations suggest that the activation of the K120-acetylation pathway may be an important tumor suppressor mechanism.

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Our current model suggests that MYST family proteins acetylate p53 at K120 after DNA damage. This acetylation somehow enhances the ability of p53 to selectively activate the transcription of apoptotic target genes. Simultaneously, acetylation of K120 provides p53 with increased apoptotic function at the mitochondria. Thus, our data suggest that K120 acetylation coordinates the nuclear and mitochondrial arms of the p53/apoptosis pathway. Three questions are being pursues. First, we will define the events that regulate K120 acetylation in response to DNA damage. Second, we will define the molecular requirement for the acetylation of K120 during the transcription of pro-apoptotic targets of p53. Finally, we will determine what essential function is played by K120 acetylation in the non-transcriptional function of p53 at the mitochondria.

Regulation of chromatin and transcription by the ubiquitin hydrolase encoded by the cancer stem cell marker USP22. The rapid increase in transcription that cells undergo in response to extracellular signals requires that sequence-specific activators dynamically overcome repressive chromatin structures at their targets. This is often accomplished by the recruitment of enzymatic complexes that modify or displace local nucleosomes. In yeast and humans, the SAGA complex is among the most thoroughly studied of these transcriptional co-activators. Previously described activities of SAGA include histone acetylation and TBP/TATA stabilization. Recently, studies, first in yeast and then humans, identified a ubiquitin hydrolase module that targets ubiquitylated H2B in yeast and both H2A and H2B in humans. Our studies of the human enzyme, termed USP22, also demonstrated that it is required for appropriate progression through the G1 phase of the cell cycle. Concurrently, USP22 was shown to be a member of an 11 gene “polycomb signature” whose expression could accurately predict human cancers with the cancer stem cell-like properties of rapid relapse, resistance to therapy and increased metastatic potential. Polycomb proteins comprise transcription co-repressor complexes, which function in part via the ubiquitylation of H2A at K119. Also in the “cancer stem cell signature” is the polycomb protein RING1b, which is the E3 ligase responsible for ubiquitylation of H2A by Polycomb Complex 1. A second link to polycomb came from studies of the drosophila ortholog of USP22 that revealed a role for this protein in blocking heterochromatin formation/position-effect-variegation, a well-established polycomb-mediated effect.

Among the issues that remain poorly understood regarding USP22 are; why is de-ubiquitylation of H2A-K119 and/or H2B-K120 required for activator-driven transcription? are histones the relevant substrates that explain the role of USP22 in transcription and cell cycle progression? what is the functional interplay between USP22 and polycomb proteins during tumorigenesis and stem cell self-renewal? and what cell cycle event requires USP22 in order for proper G1 progression? Four projects are proposed to broaden our understanding of USP22 function. These include: (1) What specific defect explains the block to activator-driven transcription in USP22 depleted cells? (2) What are the direct genomic and proteomic targets/substrates of USP22? (3) Why does USP22 depletion lead to G1 cell cycle arrest? and (4) What is the relationship between USP22 and polycomb proteins in normal and cancer stem cells? Given the genetic and biochemical links between USP22 and polycomb, it seems likely that a thorough understanding of USP22 function will provide significant insight into basic mechanisms of transcriptional regulation and the emerging area of cancer stem cell biology. 2. Current Research Projects Defining the role of MYC in the metabolic reprogramming that accompanies malignant transformation. Defining survival signals that protect tumors cells from MYC-mediated apoptosis. Understanding the link between DNA damage signals and activation of the p53 tumor suppressor protein. Characterization of enzymes that regulate epigenetic programs in normal and cancer stem cells. 3. Grant Support

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NIH/NCI R01 CA 90465 (Dr. S. McMahon) 05/01/02-04/30/13 Role of Acetyltransferases in Transformation by c-MYC NIH/NCI R21 CA152786 (Dr. S. McMahon) 07/01/10-06/30/12 Function of a novel, sirtuin-regulated acetylation site on p53. NIH/NCI R01 CA 098172 (Dr. S. McMahon) 07/01/03-06/30/09 (comp. renewal pending) Role of TRRAP in the p53-Medicated Transcription of mdm2 competitive renewal submitted 11/09 Research Support (Dr. S. McMahon) 2009-present (unrestricted) CellCentric Ltd., Chesterford Research Park, Cambridge, UK 4. Future Plans Establish Programmatic Research Projects in the following areas: a.) Molecular Determinants of Breast Cancer Stem Cell Function b.) Dissection of Survival Pathways in Human Cancer c.) DNA Damage and p53 Signaling in Prostate and Breast Cancer 5. Committees

NIH Grant Review Panel, Cancer Genetics, 2010 (ad hoc)

National Cancer Institute of Canada Review Panel

AIRC - Italian Association for Cancer Research Grant Review Panel

NIH Challenge Grant (RC1) Review Panel ZRG1 GGG-F (58)

NIH/NIEHS Outstanding New Environmental Scientist Grant Review Panel, 2010 (ad hoc)

Finland Academy Research Council for Health Grant Review Panel

NJ Commission on Cancer Research Grant Review Panel

AACR Journals - Emerging Technologies Task Force

External Examiner-Watson School of Biological Sciences, Cold Spring Harbor Laboratories

TJU-Cancer Biology Dept. Committee for Faculty Recruitment (Chair)

TJU-Kimmel Cancer Center Committee for Cancer Center Membership (Co-Chair)

Admissions Committee - Graduate Program in Cell and Developmental Biology

Organizing Committee - 15th International p53 Conference 6. Publications

Charvet C, Wissler M, Brauns-Schubert P, Wang SJ, Tang Y, Sigloch FC, Mellert H, Brandenburg M, Lindner SE, Breit B, Green DR, McMahon SB, Borner C, Gu W, Maurer U. Phosphorylation of Tip60 by GSK-3 determines the induction of PUMA and apoptosis by p53. Mol Cell. 2011 Jun 10;42(5):584-96.

Sussman RT, Zhang XY, McMahon SB. Enzymatic assays for assessing histone deubiquitylation activity. Methods. 2011 Jul;54(3):339-47. Epub 2011 Apr 12.

Heinzmann S, McMahon SB. New molecules for the treatment of pain. Curr Opin Support Palliat Care. 2011 Jun;5(2):111-5. Review.

D'Mello R, Marchand F, Pezet S, McMahon SB, Dickenson AH. Perturbing PSD-95 Interactions With NR2B-subtype Receptors Attenuates Spinal Nociceptive Plasticity and Neuropathic Pain. Mol Ther. 2011 Mar 22. [Epub ahead of print]

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Carter LM, McMahon SB, Bradbury EJ. Delayed treatment with chondroitinase ABC reverses chronic atrophy of rubrospinal neurons following spinal cord injury. Exp Neurol. 2011 Mar;228(1):149-56. Epub 2011 Jan 6.

Mellert HS, Stanek TJ, Sykes SM, Rauscher FJ 3rd, Schultz DC, McMahon SB. Deacetylation of the DNA-binding domain regulates p53-mediated apoptosis. J Biol Chem. 2011 Feb 11;286(6):4264-70. Epub 2010 Dec 9.


Aggarwal P, Vaites LP, Kim JK, Mellert H, Gurung B, Nakagawa H, Herlyn M, Hua X, Rustgi AK, McMahon SB, Diehl JA. Nuclear cyclin D1/CDK4 kinase regulates CUL4 expression and triggers neoplastic growth via activation of the PRMT5 methyltransferase. Cancer Cell. 2010 Oct 19;18(4):329-40.

Kaan TK, Yip PK, Patel S, Davies M, Marchand F, Cockayne DA, Nunn PA, Dickenson AH, Ford AP, Zhong Y, Malcangio M, McMahon SB. Systemic blockade of P2X3 and P2X2/3 receptors attenuates bone cancer pain behaviour in rats. Brain. 2010 Sep;133(9):2549-64.

Bishop T, Marchand F, Young AR, Lewin GR, McMahon SB. Ultraviolet-B-induced mechanical hyperalgesia: A role for peripheral sensitization. Pain. 2010 Jul;150(1):141-52. Epub 2010 May 15.

7. Editorial Positions Associate Editor: American Journal of Pathology (2009-present) Editorial Board Member: Journal of Biological Chemistry (2010-present) 8. Teaching Course Co-Director - Genetics 720/730:Advanced Topics in Genetics 2009-present Lecturer - Genetics 636:Regulation of Cell Cycle and Apoptosis 2007-present Lecturer - Genetics 652:Molecular Basis of Cancer 2007-present Lecturer - Biochemistry 612:Advanced Topics in Protein Function 2010-present 9. Memberships American Association for Cancer Research American Association for the Advancement of Science American Society for Microbiology American Society for Biochemistry and Molecular Biology

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Maria T. Nevalainen, M.D., Ph.D. Associate Professor

1. Description of Research Dr. Nevalainen's research program focuses on Stat transcription factors in castration-resistant growth and metastatic dissemination of prostate cancer. 2. Current Research Projects a) The molecular mechanisms underlying synergy between Stat5 and androgen receptor in prostate cancer.

b) Chemical modifications of the small-molecule pharmacological Stat5a/b inhibitor. c) Small-molecule Jak2 inhibitor AZD1480 in prostate cancer therapy in laboratory models of prostate cancer. d) Stat5 as a modifier of prostate cancer cell sensitivity to radiation therapy. e) Stat5 in metastatic behavior of prostate cancer cells in vitro and in vivo metastases models. f) Somatic changes of Stat5 genes during prostate cancer progression: Stat5a/b as an oncogene. g) Stat5a/b in promotion of prostate cancer cell growth during hypoxia. 3. Grant Support Ongoing Support: Principal Investigator: Sponsored Research Contract; “Therapeutic Targeting of Stat5 and Stat3 in Human Prostate Cancer by AZD1480; Astra Zeneca. Co-Principal Investigator: American Cancer Society Institutional Research Grant (IRG-114958), Thomas Jefferson University; Kimmel Cancer Center; (PI: Richard Pestell). Principal Investigator: Idea Development Award; “Interaction of Transcription Factor Stat5 with Androgen Receptor in Growth Promotion of Prostate Cancer”, Department of Defense Prostate Cancer Research Program. Principal Investigator: RO1-Grant (RCA11358A); “Stat5 in Progression of Prostate Cancer”, NCI, TCB Study Section. Completed Support: Principal Investigator: Idea Development Award; “Stat3 in Metastatic Progression of Prostate Cancer”, Department of Defense Prostate Cancer Research Program. Principal Investigator: New Investigator Award; “Stat5 a Therapeutic Target Protein for Prostate Cancer”, Department of Defense Prostate Cancer Research Program. Principal Investigator, Research Scholar Grant; “Androgen-Independent Growth Signaling Pathways in Prostate Cancer”, American Cancer Society.

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Collaborator, NIH U54 CA100970-01, PI; Leena Hilakivi-Clarke. Principal Investigator, Investigator Initiated Grant; “Lipid Modulation of Jak2-Stat5 Signal Transduction Pathway in Prostate Cancer”, American Institute for Cancer Research. Principal Investigator: Lombardi Comprehensive Cancer Center Developmental Funds, “Jak2 - Stat5 Signaling in Prostate Cancer”. Principal Investigator: Research Award for Prostate Cancer Research; “Stat5 as a Critical Survival Factor in Prostate Cancer”, American Cancer Society, IRG 97-152-11. 4. Future Plans a) University City Science Center “QED” funding b) RO1 “Stat5 in progression of prostate cancer” – competitive renewal. c) RC4 NCI, NIH: Development of small-molecule Stat5a/b inhibitors for prostate cancer therapy – new grant. d) RO1 “Stat5 in prostate cancer metastases – NCI, new grant. 5. Committees

2007 – Present Member, Executive Committee of Kimmel Cancer Center 2006 – Present Member, Committee on Research. 2009 – Present Member of the Research Advisory Committee, Thomas Jefferson University 2009 – Present Member of the Dean’s Faculty Forward Task Force, Thomas Jefferson University 2007 – Present Oversight Committee for Small Molecular Screening Resource (Kimmel Cancer Center) 2008 – Present Professorial Faculty Advisory Committee (Thomas Jefferson University) 2007 – Present Kimmel Cancer Center Training Committee (Chair) 2008 – Present Member of the PhD-Thesis Committee of Xiang Wang (PI: Linda Siracusa, PhD) 2009 – Present Member of the PhD- Thesis Committee of Supriya Shah (PI: Karen Knudsen, PhD) 2009 – Present Member of the PhD- Thesis Committee of Ankur Sharma (PI: Karen Knudsen, PhD)

6. Publications

Sato T, Neilson LM, Peck AR, Liu C, Tran TH, Witkiewicz A, Hyslop T, Nevalainen MT, Sauter G, Rui H. Signal transducer and activator of transcription-3 and breast cancer prognosis. Am J Cancer Res. 2011;1(3):347-355.

Koptyra M, Gupta S, Talati P, Nevalainen MT. Signal transducer and activator of transcription 5a/b: Biomarker and therapeutic target in prostate and breast cancer. Int J Biochem Cell Biol. 2011 Oct;43(10):1417-21. Epub 2011 Jun 17.

Peck AR, Witkiewicz AK, Liu C, Stringer GA, Klimowicz AC, Pequignot E, Freydin B, Tran TH, Yang N, Rosenberg AL, Hooke JA, Kovatich AJ, Nevalainen MT, Shriver CD, Hyslop T, Sauter G, Rimm DL, Magliocco AM, Rui H. Loss of nuclear localized and tyrosine phosphorylated Stat5 in breast cancer predicts poor clinical outcome and increased risk of antiestrogen therapy failure. J Clin Oncol. 2011 Jun 20;29(18):2448-58. Epub 2011 May 16.

Liao Z, Nevalainen MT. Targeting transcription factor Stat5a/b as a therapeutic strategy for prostate cancer. Am J Transl Res. 2011 Feb;3(2):133-8. Epub 2010 Nov 21.


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7. Presentations “Stat5 Signaling Pathway in Prostate Cancer Progression and as a Therapeutic Target for Advanced Prostate Cancer”. 19th Meeting of European Association of Urological Research (ESUR), October 7-9, 2010. “Curing Prostate Cancer: A Task for a Woman”. Thomas Jefferson University: “A Celebration of Jefferson Women” March 16, 2010. “Stat5 in Progression of Prostate Cancer and as a Target Protein for Therapy Development”. Columbia University, NewYork, NY. (October 30, 2009) “Stat5 in Prostate Cancer Progression: Prospects for Pharmacological Targeting”. KCC Joint Faculty Seminar Series, Thomas Jefferson University. (October 26, 2009) “Transcription Factor Stat5a/b as a Therapeutic Target Protein for Prostate Cancer”. Department of Cancer Biology, University of Massachusetts Medical School, Worcester, MA October 14, 2009 “Autocrine Prl-Jak2-Stat5 Pathway Promotes Growth and Progression of Prostate Cancer”. Gordon Conference; Hormone Action in Development and Cancer. Plymouth, NH (July 26-31, 2009) "Transcription Factor Stat5a/b as a Therapeutic Target Protein for Prostate Cancer.” AstraZeneca, Waltham, MA (April 2-3, 2009) “Transcription Factor Stat5 as a Therapeutic Target Protein for Prostate Cancer.” 5th Annual National Symposium on Prostate Cancer, Clark-Atlanta University, Atlanta, GA (March 15-17, 2009) 8. Editorial Positions 2010 – Present, Research and Reports in Biology, Member of the Honorary Editorial Board. 2010 – Present, International Journal of Clinical and Experimental Pathology, Member of the Senior Editorial Board. 2009 – Present, International Journal of Biochemistry and Cell Biology, Senior Editor. 2008 – Present, American Journal of Pathology, Member of the Editorial Board. 9. Memberships American Association for Cancer Research: 1999 – International Cytokine Society: 1999 – Endocrine Society: 1999 – American Association for the Advancement of Science: 1994 –

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Marzena J. Pedrini, Ph.D. Research Instructor

1. Description of Research The focus of my work is to understand the differences in the mechanisms responsible for peroxynitrite-dependent opening of the blood-brain barrier (BBB) during a Central Nervous System (CNS) immune/inflammatory response. The BBB is a specialization of the vasculature which is less permeable than the vasculature of the periphery. Alteration in BBB integrity is seen in

various noninflammatory neurological diseases, such as certain types of brain cancer, and in association with the invasion of circulating immune/inflammatory cells into the CNS, as is the case for multiple sclerosis. Although enhanced BBB permeability is central to the development of a pathological CNS inflammatory response, changes in BBB permeability can also occur without clinical signs during a protective CNS immune response. Using CNS trauma, the clearance of an attenuated neurotrophic virus, and experimental allergic encephalomyelitis an animal correlate of multiple sclerosis (MS) as models, we are investigating the immune mechanisms that modulate BBB function. We have shown that urate, a peroxynitrite-dependent radical scavenger, can prevent BBB permeability and cell invasion into the CNS. Currently we are concentrating on the mechanisms through which peroxynitrite-dependent radicals i) alter BBB integrity and ii) promote cell invasion through the brain parenchyma. 2. Current Research Projects

1. Characterization of the processes involved in delivering rabies virus specific immune effectors across the blood-brain barrier, an element of the response known to be deficient in animals infected with lethal rabies virus strains.

3. Grant Support

1. NIH 1 U01 AI083046-01, Principal Investigator, D.C. Hooper, Ph.D. 4. Future Plans The objective of the research program is to develop strategies to deliver therapeutic cells and factors into brain tissue in response to infection and cancer and to control this in autoimmune/non-specific conditions. Plans include obtaining independent funding for work related to MS and participate in the development of brain tumor models in the lab.

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Richard G. Pestell, MB, BS, MD, PhD, FACP, FRACP Chair, Department of Cancer Biology

1. Description of Research: Molecular mechanisms and gene therapy of breast and prostate cancer. Our research activities focus on understanding the mechanisms governing cell-cycle regulated gene transcription and the role of these proteins in tumorigenesis and differentiation. The cyclin D1 gene encodes a regulatory subunit of a holoenzyme that phosphorylates and inactivates the tumor suppressor protein pRB (retinoblastoma protein) resulting in release of the

pRB binding proteins and transcription factors, E2Fs. Several cyclin dependent kinase inhibitors (CDKI), p16/p19 block this activity of cyclin D1. Cyclin D1 plays a critical role in tumorigenesis and differentiation. Because the abundance of the cyclin D1 gene is rate-limiting in progression through the cell-cycle in cells that contain the pRB protein, we have delineated the molecular mechanisms regulating the cyclin D1 gene. We demonstrated that cyclin D1 kinase (CDK) activity and cyclin D1 promoter activity is induced by oncogenes (p21ras, Rac, dbl, v-src, Neu-also known as ErbB-2), growth factors and G-protein coupled receptors. The transcription factors (E2Fs,JUN/Fos, CREB, ATF2/ETS), coactivators (p300/CBP,Brg/Brm1) and scaffolding proteins (JIP1, caveolins) coordinate this induction. Using retroviral and lentiviral expression systems we are examining the requirement for specific cyclins and CKI for induction and progression of breast and prostate tumors induced by oncogenes. These systems are used to examine treatment synergy with conventional therapies. We have developed tissue-specific inducible transgenic expression systems and are using this transgenic approach to examine the role of cyclin D1, the CDKI in breast and prostate cancer. Using knockout mice we are examining the role of CDKI in breast cancer induced by specific oncogenes and synergy with conventional therapies.

2. Grant Support P30 CA 056036-09 (Pestell) 06/22/95-05/31/13 3 calendar NIH $2,897,417 $3,116,058/yr (Total $15,580,290) Translational Research in Cancer Cancer Center Support Grant R01 CA 075503-13 (Pestell) 06/05/98-07/31/12 0.6 calendar NIH $247,624 $382,579/yr (Total $1,913,927) Initiation and Maintenance in Mammary Tumorigenesis R01 CA 070896-14 (Pestell) 09/18/06-07/31/11 0.6 calendar NIH $192,695 $307,598/yr (Total $1,537,990) Regulation of Cyclin D1 Expression

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R01 CA 120876-01A (Lisanti) 08/03/07-07/31/12 1.2 calendar NIH $190,615 $294,500/yr (Total $1,472,500) CAV-1 Epithelial-Stromal Interactions and Breast Cancer Role: Co-Investigator (50% Pestell, 50% Lisanti) R01 CA 086072-09 (Pestell) 04/01/00-03/31/14 1.2 calendar NIH $250,000 $386,250 /yr (Total $1,931,250) Androgen Receptor Function in Prostate Cancer R01 CA 132115-02 (Pestell) 07/01/09-06/30/11 1.2 calendar NIH $207,500/yr (Total $830,000) DACH1/Eya Cell-fate Determination Factor and Mammary Tumorigenesis R01 CA 137494-01A2 (Knudsen, E) 08/01/10-01/31/15 -0- calendar NIH (Total $160,294) Impact of Cyclin D1 Isoforms in Breast Cancer P30 CA 056036-10S1 (Pestell) 06/22/95-05/31/13 -0- calendar NIH $63,390/yr (Total $63,390) Translational Research in Cancer Cancer Center Support Grant P30 CA 056036-10S2 (Pestell) 06/22/95-05/31/13 -0- calendar NIH $98,650/yr (Total $98,650) Translational Research in Cancer Cancer Center Support Grant P30 CA 056036-10S3 (Pestell) 09/01/09-08/31/10 -0- calendar NIH $154,500/yr (Total $154,500) Translational Research in Cancer Cancer Center Support Grant P30 CA 056036-10S4 (Pestell) 09/01/09-08/31/10 -0- calendar NIH $50,002/yr (Total $50,002) Translational Research in Cancer Cancer Center Support Grant P30 CA 056036-10S5 (Pestell) 09/01/09-08/31/10 -0- calendar NIH $956,943/yr (Total $956,943) Translational Research in Cancer Cancer Center Support Grant R01CA137494-01 (E. Knudsen, Pestell) 12/01/08-11/30/13 -0- calendar NIH $386,250/year (Total $1,931,250) Impact of Cyclin D1 Isoforms in Breast Cancer

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(Pestell) 07/01/06-06/30/11 -0- calendar Falk Trust $500,000 $500,000/yr (Total $2,500,000) The Role of MicroRNA Gene Expression in Human Breast Cancer 080-03800-F8 1101 (Pestell Lab) 01/01/08-12/31/10 -0- calendar Margaret Q. Landenberger Research Foundation $150,000 $150,000/yr (Total $450,000) DACH-Six-Eya Pathway in Breast Cancer Proliferation and Metastasis (Pestell) 01/01/08-12/31/10 N/A IRG-08-060-02 (Pestell) 01/01/08-12/31/11 American Cancer Society $210,000 $210,000/yr (Total $210,000) Institutional Research Grant SAP#4100034615 (Pestell) 07/26/07-12/31/10 N/A Commonwealth of PA/Dept. of Health $740,000 $740,000 (Total $740,000) Identification of a new class of genes that contributes to the development of breast cancer SAP#4100047652 (Pestell) 01/01/09- 12/31/12 N/A Commonwealth of PA/Dept. of Health $500,000 $427,800 (Total $427,800) Identification of a new class of genes that contributes to the development of breast cancer SAP#4100050910 (Pestell) 01/01/10- 12/31/13 N/A Commonwealth of PA/Dept. of Health $500,000 $553,261 (Total $553,261) Genetic Targets of Breast Tumors Initiating Cells

6. Publications July 2010 to June 2011

1. Martinez-Outschoorn, U., Balliet, R., Rivadeneira, D., Chiavarina, B., Pavlides, S., Wang, C., Whitaker-Menezes, D., Daumer, K., Lin, Z., Witkiewicz, A., Flomenberg, N., Howell, A., Pestell, R., Knudsen, E., Sotgia, F., Lisanti M.P. Oxidative stress in cancer fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle. 2010 Aug 15;9(16):3256-76. Epub 2010 Aug 28.

2. Pavlides, S., Tsirigos, A., Migneco, G., Whitaker-Menezes, D., Chiavarina, B., Flomenberg, N., Frank, P.G., Casimiro, M.C., Wang, C., Pestell R.G., Martinez-Outschoorn, U.E., Howell, A., Sotgia, F., Lisanti M.P. The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle. 2010 September 1;9(17). [Epub ahead of print].

3. Bonuccelli, G., Tsirigos, A., Whitaker-Menezes, D., Pavlides, S., Pestell, R.G., Chiavarina, B., Frank, P.G., Flomenberg, N., Howell, A., Martinez-Outschoorn, U.E., Sotgia, F., Lisanti, M.P. Ketones and lactate “fuel” tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle. 2010 Sep;9(17):3506-14. Epub 2010 Sep 21.

4. Martinez-Outschoorn U.E., Casey, T., Lin, Z., Whitaker-Menezes, D., Chiavarina, B., Zhou, J., Wang, C., Pavlides, S., Martinez-Cantarin, M.P., Capozza, F., Witkiewicz, A.K., Flomenberg, N., Howell, A., Pestell, R.G., Caro, J., Lisanti, M.P., Sotgia, F. Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment. Cell Cycle. 2010 Sep;9(17):3515-33. Epub 2010 Sep 9.

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5. Chiavarina, B., Whitaker-Menezes , D., Migneco, G., Martinez-Outschoorn, U.E., Pavlides, S., Howell, A., Tanowitz, H.B., Casimiro, M.C., Wang, C., Pestell, R.G., Grieshaber, P., Caro, J., Sotgia, F., Lisanti, M.P. HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: Autophagy drives compartment-specific oncogenesis. Cell Cycle. 2010 Sep;9(17):3534-51. Epub 2010 Sep 4.

6. Baur J.A., Chen D., Chini E.N., Chua K., Cohen H.Y., de Cabo R., Deng C., Dimmeler S., Gius D., Guarente L.P., Helfand S.L., Imai S., Itoh H., Kadowaki T., Koya D., Leeuwenburgh C., McBurney M., Nabeshima Y., Neri C., Oberdoerffer P., Pestell R.G., Rogina B., Sadoshima J., Sartorelli V., Serrano M., Sinclair D.A., Steegborn C., Tatar M., Tissenbaum H.A., Tong Q., Tsubota K., Vaquero A., Verdin E. Dietary restriction: Standing up for sirtuins. Science. 2010 Aug 27;329(5995):1012-3; author reply 1013-4.

7. Liu, M., Sakamaki, T., Casimiro, M., Willmarth, N., Quong, A., Ju, X., Ojeifo, J., Jiao, X., Yeow, W-S., Wang, C., Katiyar, S., Shirley, L., Albanese, C., Joyce, D., Pestell, R.G. The canonical NF-κB pathway governs mammary tumorigenesis in transgenic mice via tumor stem cell expansion. Cancer Res. 2010 Dec 15;70(24):10464-10473.

8. Li, Z., Jiao, X., Wang, C., Shirley, L.A., Elsaleh, H., Dahl, O., Wang, M., Soutoglou, E., Knudsen, E.S., Pestell, R.G. Alternative Cyclin D1 Splice Forms Differentially Regulate the DNA Damage Response. Cancer Res. 2010 Nov 1;70(21):8802-11. Epub 2010 Oct 12.

9. Gaughan, L., Stockley, J., Wang, N., McCracken, S.R.C., Treumann, A., Armstrong, K., Watt, K., McEwan, I.J., Wang, C., Pestell, R.G., Robson, C.N. Regulation of the androgen receptor by SET9-mediated methylation. Nucleic Acids Res. Epub 2010 Oct 19.

10. Katiyar, S., Casimiro, M., Dettin, L., Ju, X., Wagner, E.W., Tanaka, H., and Pestell, R.G. C-jun inhibits mammary apoptosis in vivo. Mol Biol Cell. 2010 Dec;21(23):4264-74. Epub 2010 Oct 6.

11. Trimmer, C., Whitaker-Menezes, D., Bonuccelli, G., Milliman, J.N., Daumer, K.M., Aplin, A.E., Pestell, R.G., Sotgia, F., Lisanti, M.P., Capozza, F. CAV1 Inhibits Metastatic Potential in Melanomas through Suppression of the Integrin/Src/FAK Signaling Pathway. Cancer Res. 2010 Oct 1;70(19):7489-99. Epub 2010 Aug 13.

12. Wu, K., Jiao, X., Li, Z., Katiyar, S., Casimiro, M.C., Yang, W., Zhang, Q., Willmarth, N.E., Chepelev, I., Crosariol, M., Wei, Z., Li, A., Zhao, K., Pestell, R.G. The Cell-Fate Determination Factor Dachshund Reprograms Breast Cancer Stem Cell Function. J Biol Chem. 2010 Oct 11. [Epub ahead of print].

13. Zhou, J., Wang, C., Zhang, W., Popov, V.M., Wang, M., Pattabiraman, N., Sune, C., Pestell, R.G. Transcription elongation regulator 1 is a co-integrator of the cell fate determination factor Dachshund homolog 1. J Biol Chem. 2010 Dec 17;285(51):40342-50. Epub 2010 Oct 18.

14. Gaughan, L., Stockley, J., Wang, N., McCracken, S.R., Treumann, A., Armstrong, K., Shaheen, F., Watt, K., McEwan, I.J., Wang, C., Pestell, R.G., Robson, C.N. Regulation of the androgen receptor by SET9-mediated methylation. Nucleic Acids Res. Epub 2010 Oct 19.

15. Marampon, F., Gravina, G.L., Di Rocco, A., Bonfili, P., Di Staso, M., Fardella, C., Polidoro, L., Ciccarelli, C., Festuccia, C., Popov, V.M., Pestell, R.G., Tombolini, V., Zani, B.M. MEKs/ERKs inhibitor U0126 increases the radiosensitivity of rhabdomyosarcoma cells in vitro and in vivo by down regulating growth and DNA repair signals. Mol Cancer Ther. 2011 Jan;10(1):159-68.

16. Martinez-Outschoorn UE, Whitaker-Menezes D, Pavlides S, Chiavarina B, Bonuccelli G, Trimmer C, Tsirigos A, Migneco G, Witkiewicz AK, Balliet R, Mercier I, Wang C, Flomenberg N, Howell A, Lin Z, Caro J, Pestell RG, Sotgia F, Lisanti MP. The autophagic tumor stroma model of cancer or "battery-operated tumor growth": A simple solution to the autophagy paradox. Cell Cycle. 2010 Nov;9(21):4297-306. Epub 2010 Nov 30.

17. Gravina, G.L., Festuccia, C., Marampon, F., Popov, V.M., Pestell, R.G., Zani, B.M., Tombolini, V. Biological rationale for the use of DNA methyltransferase inhibitors as new strategy for modulation of tumor response to chemotherapy and radiation. Mol Cancer. 2010 Nov 25;9(1):305. [Epub ahead of print]

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18. Meng, H., Tian, L., Zhou, J., Li, Z., Jiao, X., Li, W. W., Plomann, M., Xu, Z., Wang, C., and Pestell, R.G. PACSIN 2 Represses Cellular Migration through Direct Association with Cyclin D1 but not its Alternate Splice Form Cyclin D1b. Cell Cycle. 2011 Jan 1;10(1):73-81. Epub 2011 Jan 1.

19. Powell, M.J., Casimiro, M.C., Cordon-Cardo, C., He, X., Yeow, W.S., Wang, C., McCue, P., McBurney, M.W., Pestell, R.G. Disruption of a Sirt1 Dependent Autophagy Checkpoint in the Prostate Results in Prostatic Intraepithelial Neoplasia Lesion Formation. Cancer Res. 2011 Feb 1;71(3):964-75. Epub 2010 Dec 28.

20. Wang, C., Tian, L., Popov, V. M., Pestell, R.G. Acetylation and Nuclear Receptor Action. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):91-100. Epub 2010 Dec 15.

21. Trimmer C., Sotgia F., Whitaker-Menezes D., Balliet R., Eaton G., Martinez-Outschoorn U.E., Pavlides S., Howell A., Iozzo R.V., Pestell R.G., Scherer P.E., Capozza F., Lisanti M.P. Caveolin-1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal microenvironment: A new genetically tractable model for human cancer associated fibroblasts. Cancer Biol Ther. 2011 Feb 15;11(4). [Epub ahead of print]

22. Bonuccelli G, Whitaker-Menezes D, Castello-Cros R, Pavlides S, Pestell RG, Fatatis A, Witkiewicz AK, Heiden MG, Migneco G, Chiavarina B, Frank PG, Capozza F, Flomenberg N, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. The reverse Warburg Effect: Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts. Cell Cycle. 2010 Dec 14;9(10):1960-71. Epub 2010 May 15.

23. Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Tanowitz HB, Sotgia F, Lisanti MP. Stromal-Epithelial Metabolic Coupling in Cancer: Integrating Autophagy and Metabolism in the Tumor Microenvironment. Int J Biochem Cell Biol. 2011 Feb 4. [Epub ahead of print]

24. Janowski E, Jiao X, Katiyar S, Lisanti MP, Liu M, Pestell RG, Morad M. C-jun is required for TGF-β-Mediated Cellular Migration via nuclear CA

2+ Signaling. Int J Biochem Cell Biol. 2011 Mar 22.

[Epub ahead of print]

25. Li SC, Acevedo J, Schwartz PH, Wang L, Jiang H, Luo J, Pestell RG, Loudon WG, Chang AC. Mechanisms for Progenitor Cell-mediated Repair for Ischemic Heart Injury. Curr Stem Cell Res Ther. 2011 Apr 5. [Epub ahead of print]

26. Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, Wang C, Flomenberg N, Knudsen ES, Howell A, Pestell RG, Sotgia F, Lisanti MP. Ketones and lactate increase cancer cell "stemness," driving recurrence, metastasis, and poor clinical outcome in breast cancer: Achieving personalized medicine via Metabolo-Genomics. Cell Cycle. 2011 Apr 15;10(8). [Epub ahead of print]

27. Velasco-Velázquez MA, Popov VM, Lisanti MP, Pestell RG. The Role of Breast Cancer Stem Cells in Metastasis and Therapeutic Implications. Am J Pathol. 2011 May. Review.

28. Velasco-Velázquez MA, Li Z, Casimiro MC, Loro E, Homsi N, Pestell RG. Examining the role of cyclin D1 in breast cancer. Future Oncol. 2011 Jun.

29. Martinez-Outschoorn UE, Whitaker-Menezes D, Lin Z, Flomenberg N, Howell A, Pestell RG, Lisanti MP, Sotgia F. Cytokine production and inflammation drive autophagy in the tumor microenvironment: Role of stromal caveolin-1 as a key regulator. Cell Cycle. 2011 Jun 1;10(11). [Epub ahead of print].

30. Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK, Birbe RC, Howell A, Pavlides S, Gandara R, Pestell RG, Sotgia F, Philp NJ, Lisanti MP. Evidence for a stromal-epithelial “lactate shuttle” in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle. 2011 Jun 1;10(11). [Epub ahead of print].

31. DeAngelis T, Wu K, Pestell RG, Baserga R. The type 1 insulin-like growth factor receptor and resistance to DACH1. Cell Cycle. 2011 Jun 15;10(12). Report. [Epub ahead of print].

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32. Castello-Cros R, Bonnuccelli G, Molchansky A, Capozza F, Witkiewicz AK, Birbe RC, Howell A, Pestell RG, Whitaker-Menezes D, Sotgia F, Lisanti MP. Matrix remodeling stimulates stromal autophagy, “fueling” cancer cell mitochondrial metabolism and metastasis. Cell Cycle. 2011 Jun 15;10(12). [Epub ahead of print].

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Michael Prosniak, Ph.D. Research Instructor

1. Description of Research The goal of my project is to better understand the mechanisms of immunosuppression in malignant gliomas – the most common primary central nervous system neoplasms. I examined the hypothesis that malignant cells attract monocytes from the circulation into the tumor bed and promote a subset to differentiate into M2 anti-inflammatory macrophages. To test this

hypothesis I analyzed the expression of tumor-specific and immune cell molecular markers in tissue specimens from patients with low and high-grade malignant gliomas. Different methods, including quantitative reverse transcriptase-polymerase chain reaction (QRT-PCR), immunohistochemical and FACS analysis were utilized. The results obtained suggest that M2-macrophages may have an important contribution to immunosuppression observed in patients with high-grade gliomas. 2. Current Research Projects PI: D. Andrews Co-investigators: Dr. D.C. Hooper, Dr. L. Harshyne, Dr. P. Flomenberg Private grant: Paparone Foundation Period: 2002 through 2010 years Purpose: Establishment of prospective archival database including microarray analyses for patients with malignant primary brain tumors. Amount: $50 000 per year per lab 3. Future Plans I will continue to study the molecular mechanisms of immunosuppression and try to determine the origin of subsets of cells produced anti-inflammatory and immunosuppressive cytokine IL-10.

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Andrew A. Quong Associate Professor

Current Academic Appointment Cancer Biology Secondary Appointment Otolaryngology Description of Research

My laboratory is focused in two areas. In the first, we are interested in the role of kinases in migration and invasion and in particular their role in breast cancer metastasis. In the second, we are interested in developing new assays for the early diagnosis, measurement of response to therapy and stratification of patients to therapy. In both of these areas we use mass spectrometry and high-pressure liquid chromatography to identify changes in protein levels. In addition, we are developing new computational techniques to analyze these large datasets that will provide new insight into the mechanisms of the changes in the observed cellular phenotype. Current Research Projects Systems Approach to Predicting Response to Combination Therapy Breast Cancer Metastasis: The Role of Cyclin D1 Diagnostic and Prognostic Tests for Breast Cancer Estrogen Receptor, BRCA1 and Tamoxifen Response Proteomics of Papillary Thyroid Cancer Grant Support Pa Department of Health, Breast Cancer Research Foundation, NCI Publications

Liu, M., Sakamaki, T., Casimiro, M., Willmarth, N., Quong, A., Ju, X., Ojeifo, J., Jiao, X., Yeow, W-S., Wang, C., Katiyar, S., Shirley, L., Albanese, C., Joyce, D., Pestell, R.G. The canonical NF-κB pathway governs mammary tumorigenesis in transgenic mice via tumor stem cell expansion. Cancer Res. 2010 Dec 15;70(24):10464-10473.

Teaching Proteomics Committees Jefferson Medical College Committee on Research Memberships AACR, ASBMB, ASMS

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Hallgeir Rui, M.D., Ph.D. Professor


Dr. Rui has made a series of contributions to increased understanding of the molecular mechanisms of signal transduction by receptors for prolactin and related cytokines and hormones. Dr. Rui was the first to isolate a prolactin receptor-associated tyrosine kinase, and to identify this molecule as Janus kinase-2. Dr. Rui’s laboratory has maintained a focus on prolactin receptor function with a primary goal of understanding the role of downstream Jak-Stat pathways and their aberrations in breast cancer. Progress

includes recognition of the prolactin-induced Jak2-Stat5 pathway as a pro-differentiation pathway in human breast cancer, which during progression of human breast cancer is aberrantly regulated. Activation of Stat5 is a highly favorable prognostic marker in node-negative breast cancer and an invasion-suppressive role of Stat5 in human breast cancer may explain the mechanism of the favorable prognosis associated with active Stat5 in early stage breast cancer. Efforts to study the gene targets of Stat5a and Stat5b are ongoing. Dr. Rui and his team have also invented and applied a new technology to generate high density tissue arrays for high-through-put in situ biomarker studies. This technology is being combined with in situ quantitative immunoprofiling of tumors. Dr. Rui is the PI of a $6.7 million, 5 year Promise Grant from Komen for the Cure to classify breast cancer tumors based on expression of druggable target proteins for improved personalized cancer care. Dr. Rui is also supported by NCI to explore the utility of hormonally humanized mice engineered by the laboratory for improved drug response testing of human breast cancer in vivo.


“Therapy-relevant Stratification of Breast Cancer Patients: Integrating Pathology and Biomarker Analyses” (PI: Rui, H.)

The Aims of this project are 1) to use quantitative immunohistochemistry to map expression levels of a panel of 250 therapy-relevant markers across 5,000 clinical breast cancer specimens, and 2) carry out a biomarker-driven phase I/II clinical trial of the combined growth factor inhibitor and anti-angiogenic agent, motesanib.

“Experimental Modeling of Human Breast Cancer in Mice” (PI: Rui, H.) The goal of this project is to explore the utility of human prolactin expressing mice as a recipient for human breast cancer xenotransplants. Specific Aims: 1) Determine the effect of physiological levels of circulating human prolactin on growth and biology of established metastasis-derived human breast cancer lines in vivo; 2) Determine the role of human PRL and the stability of PRL receptors in modulating the sensitivity of human breast cancer cells to anti-cancer drugs; 3) Establish new transplantable human breast cancer models and evaluate hPRL mice as recipients for primary breast cancer directly from patients.

“Stat5 as a gatekeeper in human breast cancer metastasis” (PI: Rui, H.) The goal of this project is to use in vitro and in vivo approaches to experimentally test the hypothesis that Stat5 acts as a suppressor of metastatic escape of tumor cells from primary breast cancer. The studies do not aim to determine the causes of loss of active Stat5 in breast cancer. The studies maintain a strict focus on Jak2-Stat5 and do not do not investigate the role of other signaling pathways in breast cancer. Specific Aims: 1) Determine the correlation between Stat5 activation in clinical breast cancer and outcome, 2) Investigate whether Stat5 activation has invasive suppressive effects in breast cancer, 3)

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use Jak2 mammary cells and to determine whether Jak2 affects invasion and metastasis of breast cancer in vivo.

“Regulation of CXCR4 Signaling” (PI: Benovic, J.) The goal of this project is to investigate the role of CXCR4 signaling in breast cancer growth and progression involving tumor array analyses of clinical specimens. The Aim related to Dr. Rui is to study these molecules in clinical breast cancer specimens, to determine whether CXCR4 signaling is correlated with increased tumor invasion and higher grade.

“CAV-1, Stat5a Signaling and Estrogen-Dependent Breast Cancer” (PI: Lisanti, M.) The Aim related to Dr. Rui’s effort is whether to investigate in clinical specimens whether mutation/loss of Cav-1 is associated with increased activation of Stat5 and ER expression.

“CAV-1, A Novel Mammary Gland Tumor Suppressor Gene” (PI: Sotgia, F.) The goal of this proposal is to investigate the role of Caveolin-1 as a regulator of Jak2-Stat5 signaling and tumorigenesis in mammary gland cancer. The Aim related to Dr. Rui’s involvement is to determine levels of Cav-1 and other markers of invasive phenotype in clinical human breast cancer.

3. Grant Support Susan G. Komen for the Cure Promise Award $6,700,000 ($ 1,300,000/yr) 01/08/10 - 01/07/15 Therapy-relevant Stratification of Breast Cancer Patients: Integrating Pathology and Biomarker Analyses PI – Rui. 12% effort. NIH R01 CA118740 $1,000,000 ($200,000/yr) 04/01/08 - 03/31/13 Experimental Modeling of Human Breast Cancer in Mice. PI – Rui. 20% effort. Susan G. Komen Foundation Award KG070129 $180,000 ($ 60,000/yr) 07/01/08 - 06/30/11 Humanized Mouse Model for Analysis of Human Breast Cancer Xenotransplants PI- Rui. PA Breast Cancer Coalition Award #08-2008-02 $ 50,000 07/01/09-06/30/10 Control of Stat5 activity in breast cancer. PI- Rui. One year bridge funding for project reviewed favorably by NCI. NIH 5 R01 129626-03 $ 250,000 07/01/07-06/30/12 Regulation of CXCR4 Signaling PI - Benovic, J., Co-Investigator 5% effort. NIH 5 R01 CA098779 $ 250,000 07/01/07-06/30/12 CAV-1, Stat5a Signaling, and Estrogen-Dependent Breast Cancer PI - Lisanti, M., Co-Investigator. 5% effort. American Cancer Society RSG-08-081-01-MGO $ 200, 000 01/01/08-12/31/11 CAV-1, A Novel Mammary Gland Tumor Suppressor Gene PI – Sotgia, F. Co investigator at 5% effort.

4. Future Plans Future plans center on building on established collaborations with surgeons, medical oncologists, pathologists, biostatisticians, and bioinformaticists to accelerate the translational aspects of the laboratory’s research. 1) Therapy-relevant profiling of protein networks in breast cancer and other cancers; 2) strengthened focus on bioinformatics and biomedical informatics to cope with complex biological and clinical datasets; and 3) facilitate new biomarker-guided clinical trials at KCC that will involve rational recruitment of patients who are likely responders to new targeted therapies.

5. Committees TJU/KCC Committees

Kimmel Cancer Center Executive Committee, Member

Leader, Kimmel Cancer Center Endocrine Mechanisms and Hormone Action Program

MD/PhD Graduate Program oversight committee, member

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Cell Biology and Development Graduate Program, member

Cell Biology and Development Graduate Program oversight committee, member

Faculty Search Committee, Department of Cancer Biology, member

Faculty Search Committee, Cancer Prevention, Control and Population Science, member Department Review, University Review Committee for Department of Microbiology and Immunology

6. Publications

Sato T, Neilson LM, Peck AR, Liu C, Tran TH, Witkiewicz A, Hyslop T, Nevalainen MT, Sauter G, Rui H. Signal transducer and activator of transcription-3 and breast cancer prognosis. Am J Cancer Res. 2011;1(3):347-355.

Huangfu WC, Qian J, Liu C, Liu J, Lokshin AE, Baker DP, Rui H, Fuchs SY. Inflammatory signaling compromises cell responses to interferon alpha. Oncogene. 2011 Jun 13. doi: 10.1038/onc.2011.221. [Epub ahead of print]

HuangFu WC, Qian J, Liu C, Rui H, Fuchs SY. Melanoma cell-secreted soluble factor that stimulates ubiquitination and degradation of the interferon alpha receptor and attenuates its signaling. Pigment Cell Melanoma Res. 2010 Dec;23(6):838-40.

Peck AR, Witkiewicz AK, Liu C, Stringer GA, Klimowicz AC, Pequignot E, Freydin B, Tran TH, Yang N, Rosenberg AL, Hooke JA, Kovatich AJ, Nevalainen MT, Shriver CD, Hyslop T, Sauter G, Rimm DL, Magliocco AM, Rui H. Loss of nuclear localized and tyrosine phosphorylated Stat5 in breast cancer predicts poor clinical outcome and increased risk of antiestrogen therapy failure. J Clin Oncol. 2011 Jun 20;29(18):2448-58. Epub 2011 May 16.

Li D, Zhao Y, Liu C, Chen X, Qi Y, Jiang Y, Zou C, Zhang X, Liu S, Wang X, Zhao D, Sun Q, Zeng Z, Dress A, Lin MC, Kung HF, Rui H, Liu LZ, Mao F, Jiang BH, Lai L. Analysis of MiR-195 and MiR-497 expression, regulation and role in breast cancer. Clin Cancer Res. 2011 Apr 1;17(7):1722-30. Epub 2011 Feb 24.

Michal AM, Peck AR, Tran TH, Liu C, Rimm DL, Rui H, Benovic JL. Differential expression of arrestins is a predictor of breast cancer progression and survival. Breast Cancer Res Treat. 2011 Feb 12. [Epub ahead of print]

Lee KI, Rui H, Pastor RW, Im W. Brownian dynamics simulations of ion transport through the VDAC. Biophys J. 2011 Feb 2;100(3):611-9.

Rui H, Lee KI, Pastor RW, Im W. Molecular dynamics studies of ion permeation in VDAC. Biophys J. 2011 Feb 2;100(3):602-10.

Arendt LM, Rugowski DE, Grafwallner-Huseth TA, Garcia-Barchino MJ, Rui H, Schuler LA. Prolactin-induced mouse mammary carcinomas model estrogen resistant luminal breast cancer. Breast Cancer Res. 2011 Jan 28;13(1):R11. [Epub ahead of print]

Cao X, Wang Q, Liu Q, Rui H, Liu H, Zhang Y. Identification of a luxO-regulated extracellular protein Pep and its roles in motility in Vibrio alginolyticus. Microb Pathog. 2011 Feb;50(2):123-31. Epub 2010 Dec 15.

Behling KC, Tang A, Freydin B, Chervoneva I, Kadakia S, Schwartz GF, Rui H, Witkiewicz AK. Increased SIAH expression predicts ductal carcinoma in situ (DCIS) progression to invasive carcinoma. Breast Cancer Res Treat. 2011 Oct;129(3):717-24. Epub 2010 Nov 19.

Varghese B, Swaminathan G, Plotnikov A, Tzimas C, Yang N, Rui H, Fuchs SY. Prolactin inhibits activity of pyruvate kinase M2 to stimulate cell proliferation. Mol Endocrinol. 2010 Dec;24(12):2356-65. Epub 2010 Oct 20.

Johnson KJ, Peck AR, Liu C, Tran TH, Utama FE, Sjolund AB, Schaber JD, Witkiewicz AK, Rui H. PTP1B suppresses prolactin activation of Stat5 in breast cancer cells. Am J Pathol. 2010 Dec;177(6):2971-83. Epub 2010 Oct 15.

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Jo S, Rui H, Lim JB, Klauda JB, Im W. Cholesterol flip-flop: insights from free energy simulation studies. J Phys Chem B. 2010 Oct 28;114(42):13342-8.


Richards NG, Rittenhouse DW, Freydin B, Cozzitorto JA, Grenda D, Rui H, Gonye G, Kennedy EP, Yeo CJ, Brody JR, Witkiewicz AK. HuR status is a powerful marker for prognosis and response to gemcitabine-based chemotherapy for resected pancreatic ductal adenocarcinoma patients. Ann Surg. 2010 Sep;252(3):499-505; discussion 505-6.

Rui H, Im W. Protegrin-1 orientation and physicochemical properties in membrane bilayers studied by potential of mean force calculations. J Comput Chem. 2010 Dec;31(16):2859-67.

Witkiewicz AK, Freydin B, Chervoneva I, Potoczek M, Rizzo W, Rui H, Brody JR, Schwartz GF, Lisanti MP. Stromal CD10 and SPARC expression in ductal carcinoma in situ (DCIS) patients predicts disease recurrence. Cancer Biol Ther. 2010 Aug;10(4):391-6. Epub 2010 Aug 21.

Jepkorir G, Rodríguez JC, Rui H, Im W, Lovell S, Battaile KP, Alontaga AY, Yukl ET, Moënne-Loccoz P, Rivera M. Structural, NMR spectroscopic, and computational investigation of hemin loading in the hemophore HasAp from Pseudomonas aeruginosa. J Am Chem Soc. 2010 Jul 21;132(28):9857-72.

Rui H, Cao S, Shang H, Jin P, Wang K, Zheng Y. Effects of heat treatment on internal browning and membrane fatty acid in loquat fruit in response to chilling stress. J Sci Food Agric. 2010 Jul;90(9):1557-61.


Associate Editor - American Journal of Pathology Chair or Member, thesis committee for the following students:

Member of thesis committee for Rachael Dippold, TJU. Mentor Jan Hoek.

Member of thesis committee for Stephanos Pavlides, TJU. Mentor Michael Lisanti

Member of Thesis committee for Daniele Christiano, TJU. Mentor Michael Lisanti.

Member of Thesis committee for Dayana Rivadnera, TJU. Mentor Erik Knudsen.

Chair of Thesis committee for Casey Trimmer, TJU. Mentor Michael Lisanti.

Member of PhD thesis committee for Jeffrey Schmidt, University of Nebraska Medical Center, Mentor: Kay-Uwe Wagner.

Member of Thesis committee for Jeff Dean, TJU. Mentor Erik Knudsen. Lecturing:

“Jak2 Mutations in Hematopoietic Malignancies” GE652 Molecular Basis of Cancer (2h).

“Jak-Stat signaling in Cancer.” CB611 Advanced topics in Cell Biology (4h).

8. Memberships

Endocrine Society


American Association for the Advancement of Science

Fulbright Alumni Association

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Federica Sotgia, PhD Assistant Professor


Recently, we proposed a new model for understanding the Warburg effect in tumor metabolism. Our hypothesis is that epithelial cancer cells induce the Warburg effect (aerobic glycolysis) in neighboring stromal fibroblasts. These cancer-associated fibroblasts, then undergo myo-fibroblastic differentiation, and secrete lactate and pyruvate (energy metabolites resulting from aerobic glycolysis). Epithelial cancer cells could then take up these energy-rich metabolites and use

them in the mitochondrial TCA cycle, thereby promoting efficient energy production (ATP generation via oxidative phosphorylation), resulting in a higher proliferative capacity. In this alternative model of tumorigenesis, the epithelial cancer cells instruct the normal stroma to transform into a wound-healing stroma, providing the necessary energy-rich micro-environment for facilitating tumor growth and angiogenesis. In essence, the fibroblastic tumor stroma would directly feed the epithelial cancer cells, in a type of host-parasite relationship. We have termed this new idea the "Reverse Warburg Effect." In this scenario, the epithelial tumor cells "corrupt" the normal stroma, turning it into a factory for the production of energy-rich metabolites. This alternative model is still consistent with Warburg's original observation that tumors show a metabolic shift towards aerobic glycolysis. In support of this idea, unbiased proteomic analysis and transcriptional profiling of a new model of cancer-associated fibroblasts (caveolin-1 (Cav-1) deficient stromal cells), shows the upregulation of both (1) myo-fibroblast markers and (2) glycolytic enzymes, under normoxic conditions. We validated the expression of these proteins in the fibroblastic stroma of human breast cancer tissues that lack stromal Cav-1. Importantly, a loss of stromal Cav-1 in human breast cancers is associated with tumor recurrence, metastasis, and poor clinical outcome. Thus, an absence of stromal Cav-1 may be a biomarker for the "Reverse Warburg Effect," explaining its powerful predictive value.


Previously, we proposed a new model for understanding the Warburg effect in tumorigenesis and metastasis. In this model, the stromal fibroblasts would undergo aerobic glycolysis (a.k.a., the Warburg effect)--producing and secreting increased pyruvate/lactate that could then be used by adjacent epithelial cancer cells as “fuel” for the mitochondrial TCA cycle, oxidative phosphorylation, and ATP production. To test this model more directly, we used a matched set of metabolically well-characterized immortalized fibroblasts that differ in a single gene. CL3 fibroblasts show a shift towards oxidative metabolism, and have an increased mitochondrial mass. In contrast, CL4 fibroblasts show a shift towards aerobic glycolysis, and have a reduced mitochondrial mass. We validated these differences in CL3 and CL4 fibroblasts by performing an unbiased proteomics analysis, showing the functional upregulation of 4 glycolytic enzymes, namely ENO1, ALDOA, LDHA, and TPI1, in CL4 fibroblasts. Many of the proteins that were upregulated in CL4 fibroblasts, as seen by unbiased proteomics, were also transcriptionally

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upregulated in the stroma of human breast cancers, especially in the patients that were prone to metastasis. Importantly, when CL4 fibroblasts were co-injected with human breast cancer cells (MDA-MB-231) in a xenograft model, tumor growth was dramatically enhanced. CL4 fibroblasts induced a >4-fold increase in tumor mass, and a near 8-fold increase in tumor volume, without any measurable increases in tumor angiogenesis. In parallel, CL3 and CL4 fibroblasts both failed to form tumors when they were injected alone, without epithelial cancer cells. Mechanistically, under co-culture conditions, CL4 glycolytic fibroblasts increased mitochondrial activity in adjacent breast cancer cells (relative to CL3 cells), consistent with the “Reverse Warburg Effect”. Notably, Western blot analysis of CL4 fibroblasts revealed a significant reduction in caveolin-1 (Cav-1) protein levels. In human breast cancer patients, a loss of stromal Cav-1 is associated with an increased risk of early tumor recurrence, metastasis, tamoxifen-resistance, and poor clinical outcome. Thus, loss of stromal Cav-1 may be an effective marker for predicting the “Reverse Warburg Effect” in the stroma of human breast cancer patients. As such, CL4 fibroblasts may be a new attractive model for mimicking the “glycolytic phenotype” of cancer-associated fibroblasts.

3. Grant Support Source: American Cancer Society

RSG-MGO-114786/ RSG-08-081-01-MGO Project Title: CAV-1, A Novel Mammary Gland Tumor Suppressor Gene Principal Investigator: Federica Sotgia, 50% effort Dates of Project: four years, 01/01/08-12/31/011 Total Direct Costs: $800,000 Source: Breast Cancer Alliance, Young Investigator Award

Project Title: A Lactation-Based Approach for Breast Cancer Therapy and Prevention Principal Investigator: Federica Sotgia Dates of Project: two years, 01/01/09-12/31/011 Total Direct Costs: $125,000

4. Future Plans

Loss of stromal caveolin 1 (Cav-1) is a novel biomarker for cancer associated fibroblasts that predicts poor clinical outcome in breast cancer and DCIS patients. We hypothesized that epithelial cancer cells may have the ability to drive Cav-1 down-regulation in adjacent normal fibroblasts, thereby promoting the cancer associated fibroblast phenotype. To test this hypothesis directly, we are developing a novel co-culture model employing i) human breast cancer cells (MCF7), and ii) immortalized fibroblasts (hTERT-BJ1), which are grown under defined experimental conditions. Importantly, co-culture of immortalized human fibroblasts with MCF7 breast cancer cells leads to Cav-1 down-regulation in fibroblasts. These results were also validated using primary cultures of normal human mammary fibroblasts co-cultured with MCF7 cells. In this system, we can show that Cav-1 down-regulation is mediated by lysosomal degradation, as pre-treatment with lysosome-specific inhibitors rescues Cav-1 expression. Functionally, fibroblasts co-cultured with MCF7 breast cancer cells acquire a cancer associated

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fibroblast phenotype, characterized by Cav-1 down-regulation, increased expression of myofibroblast markers and extracellular matrix proteins, and constitutive activation of

TGF /Smad2 signaling. siRNA-mediated Cav-1 down-regulation mimics several key changes that occur in co-cultured fibroblasts, clearly indicating that a loss of Cav-1 is a critical initiating factor, driving stromal fibroblast activation during tumorigenesis. As such, this co-culture system can now be used as an experimental model for generating “synthetic” cancer associated fibroblasts (CAFs). More specifically, these “synthetic” CAFs could be used for drug screening to identify novel therapeutics that selectively target the Cav-1-negative tumor micro-environment. Our findings also suggest that chloroquine, or other lysosomal inhibitors, may be useful as anti-cancer agents, to therapeutically restore the expression of stromal Cav-1 in cancer associated fibroblasts.

5. Committees Co-Director, Translational Research Core Facility, Kimmel Cancer Center, Jefferson University Member, Molecular Biology and Genetic Program, Kimmel Cancer Center, Jefferson University

6. Publications

Castello-Cros R, Bonnuccelli G, Molchansky A, Capozza F, Witkiewicz AK, Birbe RC, Howell A, Pestell RG, Whitaker-Menezes D, Sotgia F, Lisanti MP. Matrix remodeling stimulates stromal autophagy, "fueling" cancer cell mitochondrial metabolism and metastasis. Cell Cycle. 2011 Jun 15;10(12):2021-34. Epub 2011 Jun 15.

Sotgia F, Martinez-Outschoorn UE, Lisanti MP. Mitochondrial oxidative stress drives tumor progression and metastasis: should we use antioxidants as a key component of cancer treatment and prevention? BMC Med. 2011 May 23;9:62.

Martinez-Outschoorn UE, Whitaker-Menezes D, Lin Z, Flomenberg N, Howell A, Pestell RG, Lisanti MP, Sotgia F. Cytokine production and inflammation drive autophagy in the tumor microenvironment: role of stromal caveolin-1 as a key regulator. Cell Cycle. 2011 Jun 1;10(11):1784-93. Epub 2011 Jun 1.

Whitaker-Menezes D, Martinez-Outschoorn UE, Lin Z, Ertel A, Flomenberg N, Witkiewicz AK, Birbe RC, Howell A, Pavlides S, Gandara R, Pestell RG, Sotgia F, Philp NJ, Lisanti MP. Evidence for a stromal-epithelial "lactate shuttle" in human tumors: MCT4 is a marker of oxidative stress in cancer-associated fibroblasts. Cell Cycle. 2011 Jun 1;10(11):1772-83. Epub 2011 Jun 1.

Witkiewicz AK, Kline J, Queenan M, Brody JR, Tsirigos A, Bilal E, Pavlides S, Ertel A, Sotgia F, Lisanti MP. Molecular profiling of a lethal tumor microenvironment, as defined by stromal caveolin-1 status in breast cancers. Cell Cycle. 2011 Jun 1;10(11):1794-809. Epub 2011 Jun 1.

Martinez-Outschoorn UE, Pavlides S, Sotgia F, Lisanti MP. Mitochondrial biogenesis drives tumor cell proliferation. Am J Pathol. 2011 May;178(5):1949-52. No abstract available.

Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, Wang C, Flomenberg N, Knudsen ES, Howell A, Pestell RG, Sotgia F, Lisanti MP. Ketones and lactate increase cancer cell "stemness," driving recurrence, metastasis and poor clinical outcome in breast cancer: achieving personalized medicine via Metabolo-Genomics. Cell Cycle. 2011 Apr 15;10(8):1271-86.

Martinez-Outschoorn UE, Prisco M, Ertel A, Tsirigos A, Lin Z, Pavlides S, Wang C, Flomenberg N, Knudsen ES, Howell A, Pestell RG, Sotgia F, Lisanti MP. Ketones and lactate increase cancer cell "stemness," driving recurrence, metastasis, and poor clinical outcome in breast cancer: Achieving

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personalized medicine via Metabolo-Genomics. Cell Cycle. 2011 Apr 15;10(8). [Epub ahead of print]

Martinez-Outschoorn UE, Pavlides S, Howell A, Pestell RG, Tanowitz HB, Sotgia F, Lisanti MP. Stromal-epithelial metabolic coupling in cancer: integrating autophagy and metabolism in the tumor microenvironment. Int J Biochem Cell Biol. 2011 Jul;43(7):1045-51. Epub 2011 Feb 15.

Llaverias G, Danilo C, Mercier I, Daumer K, Capozza F, Williams TM, Sotgia F, Lisanti MP, Frank PG. Role of cholesterol in the development and progression of breast cancer. Am J Pathol. 2011 Jan;178(1):402-12. Epub 2010 Dec 23.

Trimmer C, Sotgia F, Whitaker-Menezes D, Balliet RM, Eaton G, Martinez-Outschoorn UE, Pavlides S, Howell A, Iozzo RV, Pestell RG, Scherer PE, Capozza F, Lisanti MP. Caveolin-1 and mitochondrial SOD2 (MnSOD) function as tumor suppressors in the stromal microenvironment: a new genetically tractable model for human cancer associated fibroblasts. Cancer Biol Ther. 2011 Feb 15;11(4):383-94. Epub 2011 Feb 15.

Martinez-Outschoorn UE, Whitaker-Menezes D, Pavlides S, Chiavarina B, Bonuccelli G, Casey T, Tsirigos A, Migneco G, Witkiewicz A, Balliet R, Mercier I, Wang C, Flomenberg N, Howell A, Lin Z, Caro J, Pestell RG, Sotgia F, Lisanti MP. The autophagic tumor stroma model of cancer or "battery-operated tumor growth": A simple solution to the autophagy paradox. Cell Cycle. 2010 Nov 1;9(21):4297-306. Epub 2010 Nov 30. Review.

Chiavarina B, Whitaker-Menezes D, Migneco G, Martinez-Outschoorn UE, Pavlides S, Howell A, Tanowitz HB, Casimiro MC, Wang C, Pestell RG, Grieshaber P, Caro J, Sotgia F, Lisanti MP. HIF1-alpha functions as a tumor promoter in cancer associated fibroblasts, and as a tumor suppressor in breast cancer cells: Autophagy drives compartment-specific oncogenesis. Cell Cycle. 2010 Sep 1;9(17):3534-51. Epub 2010 Sep 4.

Pavlides S, Tsirigos A, Migneco G, Whitaker-Menezes D, Chiavarina B, Flomenberg N, Frank PG, Casimiro MC, Wang C, Pestell RG, Martinez-Outschoorn UE, Howell A, Sotgia F, Lisanti MP. The autophagic tumor stroma model of cancer: Role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle. 2010 Sep 1;9(17):3485-505.

Lisanti MP, Martinez-Outschoorn UE, Chiavarina B, Pavlides S, Whitaker-Menezes D, Tsirigos A, Witkiewicz A, Lin Z, Balliet R, Howell A, Sotgia F. Understanding the "lethal" drivers of tumor-stroma co-evolution: emerging role(s) for hypoxia, oxidative stress and autophagy/mitophagy in the tumor micro-environment. Cancer Biol Ther. 2010 Sep;10(6):537-42. Epub 2010 Sep 19. Review.

Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, Wang C, Pavlides S, Martinez-Cantarin MP, Capozza F, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG, Caro J, Lisanti MP, Sotgia F. Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment. Cell Cycle. 2010 Sep 1;9(17):3515-33. Epub 2010 Sep 9.

Bonuccelli G, Tsirigos A, Whitaker-Menezes D, Pavlides S, Pestell RG, Chiavarina B, Frank PG, Flomenberg N, Howell A, Martinez-Outschoorn UE, Sotgia F, Lisanti MP. Ketones and lactate "fuel" tumor growth and metastasis: Evidence that epithelial cancer cells use oxidative mitochondrial metabolism. Cell Cycle. 2010 Sep 1;9(17):3506-14. Epub 2010 Sep 21.

Martinez-Outschoorn UE, Balliet RM, Rivadeneira DB, Chiavarina B, Pavlides S, Wang C, Whitaker-Menezes D, Daumer KM, Lin Z, Witkiewicz AK, Flomenberg N, Howell A, Pestell RG, Knudsen ES, Sotgia F, Lisanti MP. Oxidative stress in cancer associated fibroblasts drives tumor-stroma co-evolution: A new paradigm for understanding tumor metabolism, the field effect and genomic instability in cancer cells. Cell Cycle. 2010 Aug 15;9(16):3256-76. Epub 2010 Aug 28.

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Trimmer C, Whitaker-Menezes D, Bonuccelli G, Milliman JN, Daumer KM, Aplin AE, Pestell RG, Sotgia F, Lisanti MP, Capozza F. CAV1 inhibits metastatic potential in melanomas through suppression of the integrin/Src/FAK signaling pathway. Cancer Res. 2010 Oct 1;70(19):7489-99. Epub 2010 Aug 13.

Witkiewicz AK, Dasgupta A, Sammons S, Er O, Potoczek MB, Guiles F, Sotgia F, Brody JR, Mitchell EP, Lisanti MP. Loss of stromal caveolin-1 expression predicts poor clinical outcome in triple negative and basal-like breast cancers. Cancer Biol Ther. 2010 Jul;10(2):135-43. Epub 2010 Jul 7.

7. Book Chapters and Reviews (from January 2009)

Witkiewicz AK, Casimiro MC, Dasgupta A, Mercier I, Wang C, Bonuccelli G, Jasmin JF, Frank PG, Pestell RG, Kleer CG, Sotgia F, Lisanti MP. Towards a new "stromal-based" classification system for human breast cancer prognosis and therapy. Cell Cycle. 2009 Jun 1;8(11):1654-8. Gazzerro E, Sotgia F, Bruno C, Lisanti MP, Minetti C. Caveolinopathies: from the biology of caveolin-3 to human diseases. Eur J Hum Genet. 2009 Dec;17(12):1692. Bruno C, Sotgia F, Gazzerro E, Minetti C, Lisanti MP. Caveolinopathies. In: Pagon RA, Bird TC, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-.2007 May 14.

8. Editorial Positions Senior Assistant Editor, American Journal of Pathology

9. Teaching Member, Jefferson College of Graduate Studies.

10. Memberships Member, American Association for Cancer Reaserch Member, American Association for Investigative Pathology

http://www.ncbi.nlm.nih.gov/pubmed/19584897?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/19584897?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum

http://www.ncbi.nlm.nih.gov/pubmed/20301559

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Fransiscus E. Utama Research Instructor

1. Description of Research Primary research interest is in modeling human breast cancer in mice for better predictors of drugs’ efficacy and safety. Also, discovering new biomarkers to improve prediction of patients’ prognosis is being pursued.

2. Current Research Projects Generate primary human breast cancer cell lines for in vitro studies of breast cancer. 3. Future Plans Characterize abilities of the primary human breast cancer cell lines to grow in the animal model. 4. Publications

Johnson KJ, Peck AR, Liu C, Tran TH, Utama FE, Sjolund AB, Schaber JD, Witkiewicz AK, Rui H. PTP1B suppresses prolactin activation of Stat5 in breast cancer cells. Am J Pathol. 2010 Dec;177(6):2971-83. Epub 2010 Oct 15.

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Kongming Wu Assistant Professor

1. Description of Research: Our previous studies demonstrate that DACH1 is a potential tumor suppressor by inhibiting human breast cancer cellular proliferation, invasion and metastasis. Recent studies suggested that DACH1 block breast cancer stem cell propagation and induce stem cell differentiation. We will further analyze the molecular mechanism underlie this new function of DACH1.

2. Current Research Projects: The role of DACH1 in breast cancer

3. Grant Support: Margaret Q. Landenberger Research Foundation

4. Future Plans: The role of RDGN network in cancer initiation and progression

5. Publications:

He Y, Zhao J, Wu D, Wyckhuys KA, Wu K. Sublethal effects of imidacloprid on Bemisia tabaci (Hemiptera: Aleyrodidae) under laboratory conditions. J Econ Entomol. 2011 Jun;104(3):833-8.

DeAngelis T, Wu K, Pestell R, Baserga R. The type 1 insulin-like growth factor receptor and resistance to DACH1. Cell Cycle. 2011 Jun 15;10(12):1956-9. Epub 2011 Jun 15.

Liu Z, McNeil JN, Wu K. Flight mill performance of the lacewing Chrysoperla sinica (Neuroptera: Chrysopidae) as a function of age, temperature, and relative humidity. J Econ Entomol. 2011 Feb;104(1):94-100.

Zhang T, Gu S, Wu K, Zhang Y, Guo Y. Construction and analysis of cDNA libraries from the antennae of male and female cotton bollworms Helicoverpa armigera (Hübner) and expression analysis of putative odorant-binding protein genes. Biochem Biophys Res Commun. 2011 Apr 8;407(2):393-9. Epub 2011 Mar 21.

Reduced levels of membrane-bound alkaline phosphatase are common to lepidopteran strains resistant to Cry toxins from Bacillus thuringiensis. Jurat-Fuentes JL, Karumbaiah L, Jakka SR, Ning C, Liu C, Wu K, Jackson J, Gould F, Blanco C, Portilla M, Perera O, Adang M. PLoS One. 2011 Mar 1;6(3):e17606.

An J, Gao Y, Wu K, Gould F, Gao J, Shen Z, Lei C. Vip3Aa tolerance response of Helicoverpa armigera populations from a Cry1Ac cotton planting region. J Econ Entomol. 2010 Dec;103(6):2169-73.

Wu K. No refuge for insect pests. Nat Biotechnol. 2010 Dec;28(12):1273-5. No abstract available.

Zhou J, Liu Y, Zhang W, Popov VM, Wang M, Pattabiraman N, Suñé C, Cvekl A, Wu K, Jiang J, Wang C, Pestell RG. Transcription elongation regulator 1 is a co-integrator of the cell fate determination factor Dachshund homolog 1. J Biol Chem. 2010 Dec 17;285(51):40342-50. Epub 2010 Oct 18.


Liu C, Li Y, Gao Y, Ning C, Wu K. Cotton bollworm resistance to Bt transgenic cotton: a case analysis. Sci China Life Sci. 2010 Aug;53(8):934-41. Epub 2010 Sep 7. Review.

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Liu C, Gao Y, Ning C, Wu K, Oppert B, Guo Y. Antisera-mediated in vivo reduction of Cry1Ac toxicity in Helicoverpa armigera. J Insect Physiol. 2010 Jul;56(7):718-24. Epub 2009 Dec 27.

6. Memberships: Active member of American Association of Cancer Research

96

Zuoren Yu Assistant Professor


miRNA regulation of breast cancer tumorigenesis and metastasis 2. Current Research Projects

a) miR-17/20 regulation of breast cancer b) Cyclin D1a, D1b and D1ke transgenic mouse

c) Cyclin D1/Rb regulation of miRNA

3. Future Plans a) In vivo investigation of miRNA function on breast cancer using mice model. b) Link miRNA, cancer stem cell to EMT and metastasis of breast cancer.

Documents

JEFFERSON MEDICAL COLLEGE OF THOMAS JEFFERSON …...Dr. Mark Tykocinski Dean, Jefferson Medical College Dr. Richard G. Pestell Chair, Department of Cancer Biology Mary-Anne Wallace