BREAKING INSIGHTS

5129 Highlights from Recent Cancer Literature

REVIEWS

5131 Roles and Regulation of Long Noncoding RNAsin Hepatocellular CarcinomaLee Jin Lim, Samuel Y.S.Wong, FeiyangHuang, Sheng Lim,Samuel S. Chong, London Lucien Ooi, Oi Lian Kon,and Caroline G. Lee

5140 Value of Collaboration among Multi-DomainExperts in Analysis of High-ThroughputGenomics DataDaoud Meerzaman and Barbara K. Dunn

CANCER RESEARCH HIGHLIGHTS

5146 Targeting Semaphorin 4D in Cancer: A Look fromDifferent PerspectivesLuca Tamagnone and Giulia Franzolin

See related article, p. 5328

5149 Stearoyl CoA Desaturase Regulates Ferroptosis inOvarian Cancer Offering New TherapeuticPerspectivesMichele Carbone and Gerry Melino

See related article, p. 5355

PRIORITY REPORT

5151 miR-221 Targets QKI to Enhance the TumorigenicCapacity of Human Colorectal Cancer Stem CellsJunko Mukohyama, Taichi Isobe, Qingjiang Hu,Takanori Hayashi, Takashi Watanabe, Masao Maeda,Hisano Yanagi, Xin Qian, Kimihiro Yamashita,Hironobu Minami, Koshi Mimori, Debashis Sahoo,Yoshihiro Kakeji, Akira Suzuki, Piero Dalerba, andYohei Shimono

Significance: These findings uncover molecularmechanisms underlying the maintenance of cancer stemcell properties in colon cancer.

5159 ATMIN Is a Tumor Suppressor Gene in LungAdenocarcinomaHanna Foster, E. Josue Ruiz, Christopher Moore,Gordon W.H. Stamp, Emma L. Nye, Ningning Li,Yihang Pan, Yulong He, Julian Downward, andAxel Behrens

Significance: These findings identify ATMIN as a tumorsuppressor in LUAD; fragility at chr16q23 correlates withloss of ATMIN in human LUAD and deletion of Atminincreases tumor burden in a LUAD mouse model.

GENOME AND EPIGENOME

© 2019 American Association for Cancer Research

Comparing healthy tissues and tumor samples reveals that the testis and brain are the major tissues that preferentially expressrelevant RNAs upregulated in tumors.

5167 Identification of Coding and Long NoncodingRNAs Differentially Expressed in Tumors andPreferentially Expressed in Healthy TissuesJuan P. Unfried, Guillermo Serrano, Beatriz Su�arez,Paloma Sangro, Valeria Ferretti, Celia Prior, Loreto Boix,Jordi Bruix, Bruno Sangro, Víctor Segura, and Puri Fortes

Significance: Comprehensive analysis of coding andnoncoding genes expressed in different tumors and normaltissues, which should be taken into account to predict sideeffects from potential coding and noncoding gene-targetingtherapies.

5181 Banding Together: A Systematic Comparison ofThe Cancer Genome Atlas and the MitelmanDatabasesConnor Denomy, Samuel Germain, Bjorn Haave,Frederick S. Vizeacoumar, Andrew Freywald,Beth A. Weaver, and Franco J. Vizeacoumar

Significance: A novel in silico approach comparescytogenetic data between the Mitelman database and TCGA,highlighting the advantages and limitations of both datasets.

METABOLISM AND CHEMICAL BIOLOGY

5191 Targeting Myeloperoxidase DisruptsMitochondrial Redox Balance and OvercomesCytarabine Resistance in Human Acute MyeloidLeukemiaMohsen Hosseini, Hamid Reza Rezvani, Nesrine Aroua,Claudie Bosc, Thomas Farge, Estelle Saland,V�eronique Guyonnet-Dup�erat, Sonia Zaghdoudi,Latifa Jarrou, Cl�ement Larrue, Marie Sabatier,Pierre LucMouchel, Mathilde Gotan�egre, Marc Piechaczyk,Guillaume Bossis, Christian R�echer, andJean-Emmanuel Sarry

Significance: These findings demonstrate the role ofmyeloperoxidase in the regulation of ROS levels andsensitivity of AML cells to cytarabine, an essentialchemotherapeutic backbone in the therapy of AML.

October 15, 2019 � Volume 79 � Number 20

Cancer Research

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v

MOLECULAR CELL BIOLOGY

© 2019 American Association for Cancer Research

General RNA splicing

3’5’

AGA Exon5’SF3B7

SF3B6(p14)SF3B1

A

SF3B3

SF3B4

SF3B2

SF3A1

SF3A3

U2AF2

U2 snRNA

3’ splice site

U2

SF3B5

SF3b complex AR pre-mRNACE3

Drive malignancy

CE3AR-V7 mRNA AR mRNA

3’5’

SF3B1

SF3B3

SF3B4

SF3B2

SF3A1

SF3A3

?

SF3B2 complex

SF3B2 complex-mediated alternative RNA splicing

While the SF3b complex is critical for general RNA splicing, SF3B2 promotes inclusion of the target exon through

recognizing a specific RNA motif.

5204 SF3B2-Mediated RNA Splicing Drives HumanProstate Cancer ProgressionNorihiko Kawamura, Keisuke Nimura, Kotaro Saga,Airi Ishibashi, Koji Kitamura, Hiromichi Nagano,Yusuke Yoshikawa, Kyoso Ishida, Norio Nonomura,Mitsuhiro Arisawa, Jun Luo, and Yasufumi Kaneda

Significance: RNA splicing factor SF3B2 is essential for thegeneration of an androgen receptor (AR) variant thatrenders prostate cancer cells resistant to AR-targetingtherapy.

5218 Mitochondrial NIX Promotes Tumor Survivalin the Hypoxic Niche of GlioblastomaJinkyu Jung, Ying Zhang, Orieta Celiku, Wei Zhang,Hua Song, Brian J. Williams, Amber J. Giles,Jeremy N. Rich, Roger Abounader, Mark R. Gilbert, andDeric M. Park

Significance: NIX-mediated mitophagy regulates tumorsurvival in the hypoxic niche of glioblastomamicroenvironment, providing a potential therapeutictarget for glioblastoma.

5233 Phosphorylation of HSF1 by PIM2 InducesPD-L1 Expression and Promotes TumorGrowth in Breast CancerTingting Yang, Chune Ren, Chao Lu, Pengyun Qiao,Xue Han, Li Wang, Dan Wang, Shijun Lv, Yonghong Sun,and Zhenhai Yu

Significance: These findings identify heat shocktranscription factor 1 as a new substrate for PIM2 kinaseand establish its role in breast tumor progression.

5245 CDK4 Regulates Lysosomal Function andmTORC1 Activation to Promote Cancer CellSurvivalLaia Martínez-Carreres, Julien Puyal,Lucía C. Leal-Esteban, Meritxell Orpinell,Judit Castillo-Armengol, Albert Giralt, Oleksandr Dergai,Catherine Moret, Valentin Barquissau, Anita Nasrallah,Ang�elique Pabois, Lianjun Zhang, Pedro Romero,Isabel C. Lopez-Mejia, and Lluis Fajas

Significance: These findings uncover a novel function ofCDK4 in lysosomal biology, which promotes cancerprogression by activating mTORC1; targeting this functionoffers a new therapeutic strategy for cancer treatment.

5260 ZBTB7AMediates the Transcriptional RepressionActivity of the Androgen Receptor in ProstateCancerDong Han, Sujun Chen, Wanting Han, Shuai Gao,Jude N. Owiredu, Muqing Li, Steven P. Balk,Housheng Hansen He, and Changmeng Cai

Significance: ZBTB7A is recruited to the E2F-Rb bindingsites by AR and negatively regulates the transcriptionalactivity of E2F1 on DNA replication genes.

5272 Serine-Phosphorylated STAT3 PromotesTumorigenesis via Modulation of RNAPolymerase Transcriptional ActivityJesse J. Balic, Daniel J. Garama, Mohamed I. Saad,Liang Yu, Alison C. West, Alice J. West, Thaleia Livis,Prithi S. Bhathal, Daniel J. Gough, and Brendan J. Jenkins

Significance: These findings reveal a new transcriptionalrole and mandatory requirement for constitutive STAT3serine phosphorylation in gastric cancer.

5288 SRSF3-Regulated RNA Alternative SplicingPromotes Glioblastoma Tumorigenicity byAffecting Multiple Cellular ProcessesXiao Song, Xuechao Wan, Tianzhi Huang, Chang Zeng,Namratha Sastry, Bingli Wu, C. David James,Craig Horbinski, Ichiro Nakano, Wei Zhang, Bo Hu,and Shi-Yuan Cheng

Significance: SRSF3 is a significant regulator ofglioma-associated alternative splicing, implicatingSRSF3 as an oncogenic factor that contributes to thetumor biology of GBM.

TUMOR BIOLOGY AND IMMUNOLOGY

© 2019 American Association for Cancer Research

Moderate chemotherapy dosing can lead to optimal outcomes through balancing cytotoxicity with preserving immune state tosupport a long-term antitumor T-cell response.

Lymphodepletingchemotherapy

High dose

Moderate dose

Low dose

Effector T cells Tumor cellsRegulatory T cellsTolerized cells

5302 The Goldilocks Window of PersonalizedChemotherapy: Getting the Immune ResponseJust RightDerek S. Park, Mark Robertson-Tessi, Kimberly A. Luddy,Philip K. Maini, Michael B. Bonsall, Robert A. Gatenby,and Alexander R.A. Anderson

Significance: To maximize the synergy betweenchemotherapy and antitumor immune response,lymphodepleting therapy must be balanced in a"Goldilocks Window" of optimal dosing.

5316 Prolactin Promotes Fibrosis and PancreaticCancer ProgressionManuj Tandon, Gina M. Coudriet, Angela Criscimanna,Mairobys Socorro, Mouhanned Eliliwi, Aatur D. Singhi,Zobeida Cruz-Monserrate, Peter Bailey, Michael T. Lotze,Herbert Zeh, Jing Hu, Vincent Goffin, George K. Gittes,Andrew V. Biankin, and Farzad Esni

Significance: Prolactin is a key factor in the cross-talkbetween the stroma and neoplastic epithelium, functioning topromote fibrosis and PDAC progression.

© 2019 American Association for Cancer Research

Binding of the vascular-targeting agent anti-Sema4D to Sema4D on macrophages promotes a malignant phenotype via SDF1/CXCR4signaling.

5328 Antitumor Effects of Anti-Semaphorin 4DAntibody Unravel a Novel ProinvasiveMechanism of Vascular-Targeting AgentsIratxe Zuazo-Gaztelu, Marta P�aez-Ribes, Patricia Carrasco,Laura Martín, Adriana Soler, Mar Martínez-Lozano,Roser Pons, Judith Llena, Luis Palomero,Mariona Graupera, and Oriol Casanovas

Significance: An anti-semaphorin-4D vasculartargeting agent demonstrates antitumor and prosurvivaleffects but also unravels a novel promalignant effect involvingmacrophage-derived SDF1 that promotes tumor invasion andmetastasis, both in animal models and patients.

See related commentary, p. 5146

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5342 Heparanase Accelerates Obesity-AssociatedBreast Cancer ProgressionEsther Hermano, Rachel Goldberg, Ariel M. Rubinstein,Amir Sonnenblick, Bella Maly, Daniela Nahmias,Jin-Ping Li, Marinka A.H. Bakker, Johan van der Vlag,Israel Vlodavsky, Tamar Peretz, and Michael Elkin

Significance: This study reveals the role of heparanasein promoting obesity-associated breast cancer andprovides a mechanistically informed approach touncouple obesity and breast cancer in a rapidlygrowing population of obese patients.

5355 Stearoyl-CoA Desaturase 1 Protects OvarianCancer Cells from Ferroptotic Cell DeathLia Tesfay, Bibbin T. Paul, Anna Konstorum,Zhiyong Deng, Anderson O. Cox, Jingyun Lee,Cristina M. Furdui, Poornima Hegde, Frank M. Torti,and Suzy V. Torti

Significance: The combination of SCD1 inhibitors andferroptosis inducers may provide a new therapeuticstrategy for the treatment of ovarian cancer patients.

See related commentary, p. 5149

TRANSLATIONAL SCIENCE

© 2019 American Association for Cancer Research

Meflin+PSCs or CAFs suppress PDAC progression by inhibiting ECM remodeling; they however give rise toMeflinlow/-/α SMA+CAFs, which promote PDAC progression.

Meflin+/αSMAlow PSCs or CAFs(Cancer-restraining CAFs)

Meflin

Advanced-stage cancer

Meflinlow/-/αSMA+ CAFs

Early-stage cancer

5367 Meflin-Positive Cancer-Associated FibroblastsInhibit Pancreatic CarcinogenesisYasuyuki Mizutani, Hiroki Kobayashi, Tadashi Iida,Naoya Asai, Atsushi Masamune, Akitoshi Hara,Nobutoshi Esaki, Kaori Ushida, Shinji Mii,Yukihiro Shiraki, Kenju Ando, Liang Weng,Seiichiro Ishihara, Suzanne M. Ponik,Matthew W. Conklin, Hisashi Haga, Arata Nagasaka,Takaki Miyata, Makoto Matsuyama, Tomoe Kobayashi,Tsutomu Fujii, Suguru Yamada, Junpei Yamaguchi,Tongtong Wang, Susan L. Woods, Daniel Worthley,Teppei Shimamura, Mitsuhiro Fujishiro,Yoshiki Hirooka, Atsushi Enomoto, andMasahide Takahashi

Significance:Meflin marks and functionally contributes toa subset of cancer-associated fibroblasts that exertantitumoral effects.

5382 In Vivo Modeling of ChemoresistantNeuroblastoma Provides New Insights intoChemorefractory Disease and MetastasisOrli Yogev, Gilberto S. Almeida, Karen T. Barker,Sally L. George, Colin Kwok, James Campbell,Magdalena Zarowiecki, Dimitrios Kleftogiannis,Laura M. Smith, Albert Hallsworth, Philip Berry,Till M€ocklinghoff, Hannah T. Webber,Laura S. Danielson, Bliss Buttery, Elizabeth A. Calton,Barbara M. da Costa, Evon Poon, Yann Jamin,Stefano Lise, Gareth J. Veal, Neil Sebire,Simon P. Robinson, John Anderson, and Louis Chesler

Significance: An in vivo mouse model of high-risktreatment-resistant neuroblastoma exhibits changes in thetumor microenvironment, widespread metastases, andsensitivity to JAK1/2 inhibition.

5394 Nanoparticle Encapsulation of SynergisticImmune Agonists Enables Systemic Codeliveryto Tumor Sites and IFNb-Driven AntitumorImmunityPrabhani U. Atukorale, Shruti P. Raghunathan,Vanitha Raguveer, Taylor J. Moon, Carolyn Zheng,Peter A. Bielecki, Michelle L. Wiese, Amy L. Goldberg,Gil Covarrubias, Christopher J. Hoimes, andEfstathios Karathanasis

Significance: Systemic administration of an immuno-nanoparticle in a murine breast tumor model drives a robusttumor site–specific APC response by delivering twosynergistic immune-potentiating molecules, highlightingthe potential of nanoparticles for immunotherapy.

CONVERGENCE AND TECHNOLOGIES

© 2019 American Association for Cancer Research

An activatable and cancer-targeted hydrogen peroxide probe enables photoacoustic molecularimaging in a mouse model of breast cancer.

+ H2O2

H2O2 - reactive group

−

NRNR

H

5407 An Activatable Cancer-Targeted HydrogenPeroxide Probe for Photoacoustic andFluorescence ImagingJudith Weber, Laura Bollepalli, Ana M. Belenguer,Marco Di Antonio, Nicola De Mitri, James Joseph,Shankar Balasubramanian, Christopher A. Hunter, andSarah E. Bohndiek

Significance: This study presents the first activatable andcancer-targeted hydrogen peroxide probe for photoacousticmolecular imaging, paving the way for visualization ofhydrogen peroxide at high spatiotemporal resolution inliving subjects.

5418 Quantification and Localization of Protein–RNAInteractions in Patient-Derived Archival TumorTissueEmmeline L. Blanchard, Danae Argyropoulou,Chiara Zurla, Sushma M. Bhosle, Daryll Vanover, andPhilip J. Santangelo

Significance: This work presents an approach to sensitively,specifically, and quantitatively detect and localize nativemRNA and protein interactions for analysis of abnormalpost-transcriptional regulation in patient-derived archivaltumor samples.

POPULATION AND PREVENTION SCIENCE

5432 MALAT1 rs664589 Polymorphism InhibitsBinding to miR-194-5p, Contributing toColorectal Cancer Risk, Growth, and MetastasisShenshen Wu, Hao Sun, Yajie Wang, Xi Yang,QingtaoMeng, Hongbao Yang, Haitao Zhu,Weiyan Tang,Xiaobo Li, Michael Aschner, and Rui Chen

Significance: These findings highlight the functionalrole of MALAT1 polymorphism in colorectal cancermetastasis and survival as well as the underlyingmechanism.

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5442 High Levels of C-Reactive Protein Are Associatedwith an Increased Risk of Ovarian Cancer:Results from the Ovarian Cancer CohortConsortiumLauren C. Peres, Adrianne R. Mallen, Mary K. Townsend,Elizabeth M. Poole, Britton Trabert, Naomi E. Allen,Alan A. Arslan, Laure Dossus, Ren�ee T. Fortner,Inger T. Gram, Patricia Hartge, Annika Idahl,Rudolf Kaaks, Marina Kvaskoff, Anthony M. Magliocco,Melissa A. Merritt, J. Ramón Quirós, Anne Tjonneland,Antonia Trichopoulou, Rosario Tumino,Carla H. van Gils, Kala Visvanathan,Nicolas Wentzensen, Anne Zeleniuch-Jacquotte, andShelley S. Tworoger

Significance: C-reactive protein is involved in ovariancarcinogenesis, and chronic inflammation may beparticularly implicated in the etiology of mucinous andendometrioid carcinomas.

RESOURCE REPORT

5452 Curatopes Melanoma: A Database of PredictedT-cell Epitopes fromOverly Expressed Proteins inMetastatic Cutaneous MelanomaChristopher Lischer, Martin Eberhardt, Tanushree Jaitly,Cornelia Schinzel, Niels Schaft, Jan D€orrie,Gerold Schuler, and Julio Vera

Significance: A database is presented that predicts andscores antitumor T-cell epitopes, with a focus on tolerabilityand avoidance of severe autoimmunity, offering asupplementary epitope set for further investigation inimmunotherapy.

CORRECTION

5457 Correction: An Inhibitor of the PleckstrinHomology Domain of CNK1 SelectivelyBlocks the Growth of Mutant KRAS Cells andTumorsMartin Indarte, Roisin Puentes, Marco Maruggi,Nathan T. Ihle, Geoffrey Grandjean, Michael Scott,Zamal Ahmed, Emmanuelle J. Meuillet, Shuxing Zhang,Robert Lemos Jr, Lei Du-Cuny, Fabiana I.A.L. Layng,Ricardo G. Correa, Laurie A. Bankston,Robert C. Liddington, Lynn Kirkpatrick, andGarth Powis

EDITOR'S NOTE

5458 Editor's Note: Estrogen Receptor a PromotesBreast Cancer by Reprogramming CholineMetabolismMin Jia, Trygve Andreassen, Lasse Jensen,Tone Frost Bathen, Indranil Sinha, Hui Gao,Chunyan Zhao, Lars-Arne Haldosen, Yihai Cao,Leonard Girnita, Siver Andreas Moestue, andKarin Dahlman-Wright

RETRACTION

5459 Retraction: The Raf Inhibitor BAY 43-9006(Sorafenib) Induces Caspase-IndependentApoptosis in Melanoma CellsDavid J. Panka, Wei Wang, Michael B. Atkins, andJames W. Mier

AC icon indicates Author Choice

For more information please visit www.aacrjournals.org

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ABOUT THE COVER

Chemotherapeutic elimination (green) of the tumor is a complex challenge. Mathematicalmodeling of tumor-immune interactions reveals that optimal therapy, which may initiallyseem black and white, requires delicate navigation through a complex multidimensionallandscape personalized to each patient. Cytotoxic efficacy (purple) must be balanced withsupporting patient antitumor immune responses stimulated by lymphodepletion (blue).Optimal therapy treads an intermediate path (gold) that maintains dosing within a maximallyeffective window. The authors acknowledge the help of Dr. Chandler D. Gatenbee whoprovided coding expertise on the coloring for the image. For details, see article by Park andcolleagues on page 5302.

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