Aichi Cancer Center Research Institute

Scientific Report 2014 – 2015

Chikusa-ku, Nagoya 464-8681 Japan

(The Cover) The Aichi Cancer Center Research Institute Main Building, photo courtesy of Dr. Keitaro Matsuo Published by Dr. Taira Kinoshita President Aichi Cancer Center Research Institute 1-1 Kanokoden, Chikusa-ku, Nagoya 464-8681, Japan Telephone: 052-762-6111 Facsimile: 052-763-5233 Editorial Committee Dr. Masahiro Aoki (Division of Molecular Pathology) Dr. Keiichiro Sakuma (Division of Molecular Pathology) Dr. Malcolm A. Moore, English Editor Printed by Nagoya University COOP 1 Furoucho, Chikusa-ku, Nagoya 464-0814, Japan

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Contents Preface

Taira Kinoshita 1 Organization of the Aichi Cancer Center Research Institute 2 Scientific Reports Division of Epidemiology and Prevention

General Summary 5 1. Descriptive epidemiology 1.1. Advances and set-backs/persisting problems in the treatment of lymphoma 6 and myeloma patients: Analysis of survival using population-based cancer registry data in Japan from 1993 to 2006 Chihara, D., Ito, H., Izutsu, K., Hattori, M., Nishino, Y., Ioka, A., Matsuda, T., and Ito, Y. 1.2. Declining trends in prevalence of Helicobacter pylori infection by birth-year in a Japanese population Watanabe, M., Ito, H., Hosono, S., Oze, I., Ashida, C., Tajima, K., Katoh, H., Matsuo, K., and Tanaka, H. 2. The hospital-based epidemiologic research program at Aichi Cancer Center

(HERPACC) study 2.1. Impact of metallothionein gene polymorphisms on the risk of lung cancer 7 in a Japanese population

Ito, H., Nakane, H., Hirano, M., Hosono, S., Oze, I., Matsuda, F., Tanaka, H., Matsuo, K.

2.2. Polymorphisms in CYP19A1, HSD17B1 and HSD17B2 genes and serum sex hormone levels among postmenopausal Japanese women Hosono, S., Ito, H., Oze, I., Higaki, Y., Morita, E., Takashima, N., Suzuki, S., Shimatani, K., Mikami, H., Ohnaka, K., Ozaki, E., Katsuura-Kamano, S., Kubo, M., Nagata, C., Naito, M., Hamajima, N., Tanaka, H., and for the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study Group. 2.3. Comparison of circulating miRNA levels between gastric cancer patients 8 and non-cancer controls Oze, I., Nagasaki, H., Shimada, S., Akiyama, Y., Hosono, S., Ito, H., Watanabe, M.,Yatabe, Y., Tanaka, H., Matsuo, K., Yuasa, Y. 3. Tobacco control 3.1. Factors associated with successful and maintained quit smoking status among 9 patients who received Japanese smoking cessation therapy Tanaka, H., Taniguchi, C., Saka, H., Oze, I., Tachibana, K., Nozaki, Y., Suzuki, Y., Suehisa, H., Sakakibara, H. Division of Oncological Pathology

General Summary 11 1. Coxsackie and adenovirus receptor – a novel negative regulator of RhoA associated kinase (ROCK) - is a critical regulator of survival and growth of oral

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squamous carcinoma cells Saito, K., Sakaguchi, M., Iioka, H., Matsui, M., Nakanishi, H., Huh N., and Kondo, E. 2. A extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor 12 growth of human malignant melanoma cells Ruma IMW, Putranto EW, Kondo E, Watanabe R, Saito K, Inoue Y, Yamamoto K, Nakata S, Kaihata M, Murata H and Sakaguchi M 3. Development of a New Rapid Isolation Device for Circulating Tumor Cells 13 (CTCs) using 3D Palladium Filter and its Application for Genetic Analysis Yusa A, Toneri T, Masuda T, Ito S, Yamamoto S, Okochi M, Kondo N, Iwata H, Yatabe Y, Ichinosawa Y, Kinuta S, Kondo E, Honda H, Arai F, Nakanishi H. 4. New whole-body multimodality imaging of gastric cancer peritoneal metastases 14 combining fluorescence imaging with ICG-labeled antibodies and MRI in mice Ito A, Ito Y, Matsushima S, Tsuchida D, Ogasawara M, Hasegawa J, Misawa K, Kondo E, Kaneda N, Nakanishi H. Division of Molecular Oncology

General Summary 16 1. Functional differences between wild-type and mutant-type BAP1 tumor 17 suppressor against malignant mesothelioma cells Hakiri, S., Osada, H., Ishiguro, F., Murakami, H., Murakami-Tonami, Y., Yokoi, K., and Sekido, Y. 2. SMC2 regulates the transcription of DDR genes and shows synergistic phenotype with MYCN Murakami-Tonami, Y., Kishida, S., Takeuchi, I., Katou, Y., Maris, JM., Ichikawa, H., Kondo, Y., Sekido, Y., Shirahige, K., Murakami, H., and Kadomatsu, K. Division of Molecular Medicine

General Summary 20 1. Establishing prediction models of upper-aerodigestive tract cancer using molecular and environmental information Koyanagi, Y., Ito, H., Oze, I., Hosono, S., Watanabe, M., Tanaka, H., Abe, T., Shimizu, Y., Hasegawa, Y., and Matsuo, K. 2. Generation of mouse models of lymphoid neoplasms using retroviral gene 21 transduction of in vitro-induced germinal center B cells Takahara T., Arita, K., Yoshida, N., Sugiyama, T., Seto, M., and Tsuzuki, S. 3. Establishment of a new mouse model of adult T cell leukemia Kasugai-Maeda, Y., Yoshida, N., Seto, M., and Tsuzuki, S. 4. Clonal heterogeneity of lymphoid malignancies correlates with poor prognosis Katayama, M., Yoshida, N., Umino A., Kato H., Tagawa, H., Nakagawa, M., Fukuhara, N., Sivasundaram, S., Takeuchi, I., Hocking TD., Arita, K., Karube, K., Tsuzuki. S, Nakamura, S., Kinoshita T., and Seto, M. 5. Establishment of a model of YAP-driven malignant mesothelioma 22 Kakiuchi, T., Takahara, T., Kasugai-Maeda, Y., Arita, K., Yoshida, N., Karube, K., Katayama, M., Nakanishi, H., Kiyono, T., Nakamura, S., Osada, H., Sekido, Y., Seto, M., and Tsuzuki, S.

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Division of Immunology

General Summary 25 1. Identification of a naturally processed HLA-Cw7-binding peptide that 26 cross-reacts with HLA-A24-restricted ovarian cancer-specific CTLs

Demachi-Okamura, A., Yamada, E., Kondo, S., Shibata, K., Kikkawa, F., and Kuzushima, K.

2. Interaction of Vα24 iNKT cells with dendritic cells increases the therapeutic efficacy of TCR-gene modified T cells

Zhang, R., Uemura, Y., Liu, T., Ikeda, H., Okamoto, S., Tatsumi, M., Mineno, J., Shiku, H., and Kuzushima, K.

3. Cellular adjuvant properties and direct cytotoxicity in rejuvenated Vα24 invariant 27 NKT cells from human induced pluripotent stem cells

Zhang, R., Kitayama, S., Liu, R., Ueda, N., Tatsumi, M., Kaneko, S., Kuzushima, K., and Uemura, Y.

4. Depletion of DSS1, which is a member of mammalian TREX2 complex and maintains BRCA2 stability, confers breast cancer cells highly-sensitive to anti-cancer drugs through DNA damage

Gondo, N., Rezano A., Ohta, R., Kuzushima, K., Toyama, T., and Kuwahara, K. Division of Microbiology and Oncology

General Summary 30 1. Spatial regulation of Src via lipid rafts controls cancer progression

Oneyama, C., Kuwahara, A., Miyata, M., and Watanabe, R. 2. MicroRNA-mediated gene expression controls Src-related oncogenic signaling

Oneyama, C., Ninomiya, Y., Miyata, M., and Watanabe, R. 3. Clustered microRNAs of the Epstein- Barr virus cooperatively downregulate 31 an epithelial cell-specific metastasis suppressor

Kanda, T., and Miyata, M. 4. A herpesvirus specific motif of Epstein-Barr virus DNA polymerase is required 32 for efficient lytic genome synthesis

Narita, Y., Kawashima, D., Kanda, T., Tsurumi, T., and Murata, T. Division of Molecular Pathology

General Summary 34 1. An in vivo shRNA screen identifies HNRNPLL as a novel colorectal cancer metastasis suppressor Sakuma, K., Sasaki, E., Kimura, K., Komori, K., Shimizu, Y., Yatabe, Y., and Aoki, M. 2. Simultaneous inhibition of mTOR and EGFR suppresses invasion of intestinal adenocarcinoma in cis-Apc+/Δ716 Smad4+/- mice Fujishita, T., Kojima, Y., Kajino, R., Taketo, MM., and Aoki, M. 3. The MEK/ERK signaling inhibition suppresses intestinal polyp formation by reducing the stromal COX-2 and CCL2 levels Fujishita, T., Kajino, R., Kojima, Y., Taketo, MM., and Aoki, M. Division of Biochemistry

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General Summary 38 1. Ndel1 is a suppressor of primary cilia assembly

Inaba, H., Goto, H., Kasahara, K., Inoko, A., He, D., Tanigawa, N., Hayashi, Y., Kobori, K., Kumamoto, K., Yonemura, S., Goshima, N., Yamano S., Wanibuchi, H., Kiyono, T., Hirotsune, S., and Inagaki, M.

2. The ubiquitin-proteasome system controls primary cilia formation at the initial 39 step of axoneme extension

Kasahara, K., Aoki H., Kawamoto E., Kawakami Y., Kiyono T., Kawamura Y., Goshima N., and Inagaki M.

3. Cytokinetic failure induces aneuploidy and aging in vimentin Tanaka, Hir., Goto, H., Inoko, A., Hayashi, Y., Kobori, K., Tanigawa, N., Makihara, H., Izawa, I., and Inagaki, M.

4. Novel platform for integrating centrosomal functions 40 Inoko, A., Hayashi, Y., Kiyono, T., Goshima, N., and Inagaki, M.

Central Service Unit

General Summary 42 1. Relationship between risk of esophageal cancer and the number of polymorphisms in mitochondrial DNA

Kumimoto, H. Librarians Publications 1. Journals 2. Reviews and books 3. Abstracts for international conferences Records of Seminars Records of Symposium

From left to right Ms. T. Hayashi and Dr. T. Kinoshita

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Preface _______________________________________________________________________________________

It is my pleasure to share with you the 24th Scientific Report (2014-2015) of the Aichi Cancer Center

Research Institute. Since its establishment in 1964, Scientific Reports have been published biennially to document major research activities and highlight progress in and contributions to cancer research worldwide.

As illustrated on the following pages, the Research Institute consists of 8 Divisions, along with a Central Service Unit, an Animal Facility and a Laboratory of Translational Research, with overall research emphasis on three areas: cancer prevention/epidemiology; preclinical/experimental therapy; and carcinogenesis/molecular biology. In addition, the institute is affiliated with the Nagoya University Graduate School of Medicine and the Nagoya City University Graduate School of Pharmaceutical Sciences. At the present time 7 professors and 4 associated professors nominated from the chiefs and section heads of the Research Institute are engaged in education of graduate school students at the two universities. In Aichi Cancer Center Research Institute itself, a total of 62 staff members, 29 researchers and 22 research assistants, as well as 11 research residents, are now conducting a wide range of studies, together with 7 graduate school students, and approximately 25 visiting research fellows and 40 temporary research assistants.

The major areas being pursued are as follows: - descriptive and analytical epidemiology of cancers - primary and secondary prevention of cancer - molecular pathogenesis of intractable malignancies - peptide-based anti-cancer DDS technology - molecular oncology of malignant mesotheliomas and lung cancers - identification and characterization of new cancer-associated genes - molecular biology of translocation-junction genes in hematopoietic tumors - molecular epidemiology and it's application in clinical practice/prevention - basic studies for cancer immunotherapy - genetic approaches to breast cancer susceptibility and prognosis - molecular basis of oncogene-mediated cancer progression - human viral oncogenesis - molecular mechanisms of colorectal cancer metastasis - pathophysiology of cancer cachexia - molecular mechanisms of cell proliferation and movement - ciliary dynamics in carcinogenesis

More detailed descriptions of the individual research topics of each Division appear in the contents of this report. It is our sincere hope that the activities of the Institute will make a major contribution to elucidation of the mechanisms of carcinogenesis and to development of novel clinical applications in cancer diagnosis, treatment and prevention.

Finally, I would like to express my deep appreciation to the Aichi Prefectural Government for the continuous support received since this Institute was founded in 1964. Granting support from the Ministry of Education, Science, Sports, Culture and Technology, the Ministry of Health, Labor, and Welfare, and the Ministry of Economy, Trade and Industry, as well as other related organizations in Japan, is also gratefully acknowledged.

January, 2016

Taira Kinoshita, M.D., M.P.H., D.M.Sci. Acting Director, President

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Organization of the Aichi Cancer Center Research Institute _______________________________________________________________________________________

SCIENTIFIC REPORTS

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From left to right

First row: Dr. I. Oze, Dr. S. Hosono, Dr. H. Tanaka, Dr. H. Ito, Ms. M. Watanabe, Dr. H. Nakagawa Second row: Ms. N. Kawamura, Ms. A. Yoshida, Ms. S. Nimura, Ms. I. Kato, Ms. R. Niwa, Dr. S. Inoue, Ms. Y. Mano, Ms. Y. Sugino Third row: Ms. A. Hiraiwa, Ms. T. Nishiwaki, Ms. M. Miyoshi, Ms. Y. Taniguchi, Ms. K.

Koide, Ms. M. Kawaguchi, Ms. S. Inui, Ms. T. Ito

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Division of Epidemiology and Prevention ________________________________________________________________________________

Hideo Tanaka, M.D., PhD. Chief Hidemi Ito, M.D., PhD., M.P.H. Section Head (as of April 2009) Satoyo Hosono, M.D., PhD. Senior Researcher (as of April 2009) Isao Oze, M.D. Senior Researcher (as of April 2012) Koichi Fukumoto, M.D. Research Resident (Until March 2014) Dai Chihara, M.D., PhD. Research Resident (Until June 2014) Hiroko Nakagawa, M.D., PhD. Research Resident (as of April 2014) Shusaku Inoue, M.D. Research Resident (as of April 2015) Miki Watanabe, MSc. Research Assistant (as of April 2006) Tomoko Ito. Research Assistant (as of April 2012) Yasuo Morishima, M.D. PhD. Researcher (as of April 2011) Keitaro Matsuo, M.D., PhD., S.M. Researcher (until June 2015) Visiting Trainees Daisuke Kawakita, M.D., PhD. Nagoya City University Hideo Nakane, PhD. Toyota Central R&D Labs., Inc. Dai Chihara, M.D. Nagoya University Graduate School of Medicine Akiyo Yoshimura, M.D. Aichi Cancer Center Hospital Satoko Morishima, M.D, PhD. Fujita Health University School of Medicine Chie Taniguchi, MSc. Sugiyama Jogakuen University Michiyo Yamaguchi.

General Summary

The current research activities of the Division of Epidemiology and Prevention cover the following three subjects: (1) descriptive epidemiology of cancer incidence, mortality and survival using data from the Aichi Prefectural Cancer Registry and other population-based registries in a collaborative study; (2) analytical epidemiology based on the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC) to determine risk and protective factors for cancer, with a particular focus on gene-environmental interactions; and (3) epidemiologic studies for tobacco control. Our main results in 2014 and 2015 were that: 1) in a review of cancer-registry data of patients with lymphoma and myeloma in Japan from 1993 to 2006, we observed that relative survival had improved for cases of Hodgkin lymphoma, diffuse large B-cell lymphoma and follicular lymphoma. In contrast, there was no significant improvement in survival with peripheral T-cell lymphoma, adult T-cell leukemia/lymphoma or multiple myeloma; 2) a dramatic decline in the prevalence of H. pylori infection was observed in those born between 1949 and 1961 in the Japanese population, which should contribute to projected future trend of decreasing gastric cancer incidence in Japan; 3) polymorphisms in the metallothionein gene were found to be moderately associated with risk of lung cancer and that the association was modified by lifestyle factors; 4) CYP19A1 and HSD17B2 polymorphisms might be associated with circulating sex hormone levels in Japanese postmenopausal women, independent of current BMI; 5) plasma miR-103, miR-107 and miR-194 levels are not useful biomarkers for detecting diffuse-type gastric cancer; 6) having a higher self-efficacy of quitting smoking and varenicline use are associated with success of Japanese smoking cessation therapy (SCT), while a strong desire to smoke is a risk factor for obstructing maintained cessation during 12 months after the end of SCT.

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1. Descriptive epidemiology 1.1. Advances and set-backs/persisting problems in the treatment of lymphoma and myeloma patients: Analysis of survival using population-based cancer registry data in Japan from 1993 to 2006 Chihara, D.*1, Ito, H.*2, Izutsu, K.*3, Hattori, M.*4, Nishino, Y.*5, Ioka, A.*6, Matsuda, T.*7, and Ito, Y.*6 There have been significant advances in the treatment of patients with lymphoma and myeloma. Although improvements in survival outcome have been addressed by clinical trials, such studies may not adequately take into account changes in survival in the general patient population over time. Therefore, we reviewed the cancer-registry data of patients with lymphoma and myeloma in Japan from 1993 to 2006 and estimated relative survival (adjusted for competing causes of death in same-age members of the general population) according to three periods of diagnosis (1993-1997, 1998-2002 and 2003-2006). We also estimated conditional 5-year relative survival (5-year survival rate of patients who have survived 5 years). A total of 26,141 patients were reviewed and analyzed. Relative survival improved for Hodgkin lymphoma (HL, N = 853, +20% improvement), diffuse large B-cell lymphoma (DLBCL, N = 4,919, +14% improvement) and follicular lymphoma (FL, N = 1,333, +13% improvement). In contrast, we found no significant improvement in survival since 1993 with peripheral T-cell lymphoma (PTCL, N = 667, +4% improvement), adult T-cell leukemia/lymphoma (ATLL, N = 2,166, -5% improvement) or multiple myeloma (MM, N = 4,914, -2% improvement). Conditional 5-year survival of HL, DLBCL, FL, PTCL, ATLL and MM was 88, 87, 79, 63, 53 and 45%, respectively. Relative survival of patients with HL, DLBCL and FL significantly improved from 1993 to 2006 in Japan; in contrast, no improvement was seen with other related diseases, suggesting unmet needs for novel treatment strategies. *1Department of Lymphoma and Myeloma, MD Anderson Cancer Center *2Department of Epidemiology, Nagoya University Graduate School of Medicine *3Department of Hematology, Toranomon Hospital *4Department of Cancer Therapy Center, Fukui Prefectural Hospital *5Division of Cancer Epidemiology and Prevention, Miyagi Cancer Center Research Institute *6Center for Cancer Control and Statistics, Osaka Medical Center for Cancer and Cardiovascular Diseases *7Division of Surveillance, Center for Cancer Control

and Information Services, National Cancer Center 1.2. Declining trends in prevalence of Helicobacter pylori infection by birth-year in a Japanese population Watanabe, M., Ito, H., Hosono, S., Oze, I., Ashida, C.*1, Tajima, K.*2, Katoh, H.*1, Matsuo, K.*3, and Tanaka, H. The age-standardized incidence and mortality rates for gastric cancer have been decreasing in Japan. This is likely to be due to some extent to a decrease in prevalence of Helicobacter pylori (H. pylori) infection, a major risk factor for neoplasia in the stomach. Our aim was to characterize the trends in prevalence of H. pylori infection focusing on birth-year in a Japanese population. We conducted a cross-sectional study that included 4,285 subjects who were born from 1926 to 1989. We defined H. pylori infection by serum H. pylori antibody titer. Individuals having H. pylori infection and those with negative H. pylori antibody titer but positive pepsinogen test were defined as high-risk individuals for gastric cancer. We estimated the birth-year percent change (BPC) of the prevalence by Joinpoint regression analysis. The prevalence of H. pylori infection among the subjects born from 1927 to 1949 decreased from 54.0% to 42.0% with a BPC of -1.2% (95%CI: -1.6% to -0.8%). This was followed by a rapid decline in those born between 1949 (42.0%) and 1961 (24.0%) with a BPC of -4.5% (95%CI: -6.0% to -3.0%), and a slower decline in those born between 1961 (24.0%) and 1988 (14.0%) with a BPC of -2.1% (95%CI: -3.3% to -0.8%). The proportion of high-risk individuals for gastric cancer among the subjects born from 1927 to 1942 decreased from 62.0% to 55.0% with a BPC of -0.8% (95%CI: -1.4% to -0.1%). A subsequent rapid declining trend was observed in those born between 1942 (55.0%) and 1972 (18.0%) with a BPC of -3.6% (-3.9% to -3.2%), and then it became stable. Thus a dramatic decline in the prevalence of H. pylori infection was observed in those born between 1949 and 1961. As the population attributable fraction (PAF) for H. pylori infection with gastric cancer is considerably large, this declining trend in prevalence of H. pylori infection would contribute to a projected future reduction in gastric cancer incidence in Japan. *1FALCO biosystems Ltd. Tokai-chuo Laboratory *2Department of Public Health and Occupational Medicine, Mie University Graduate School of Medicine *3Division of Molecular Medicine, Aichi Cancer Center Research Institute

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2. The hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC) study 2.1. Impact of metallothionein gene polymorphisms on the risk of lung cancer in a Japanese population Ito, H.*1, Nakane, H.*2, Hirano, M.*3, Hosono, S., Oze, I., Matsuda, F.*4, Tanaka, H.*1, Matsuo, K.*5 Metallothioneins (MTs) are cysteine-rich proteins that act as antioxidants. A case-control study was conducted to assess the effects of gene polymorphisms in the MT region on the risk of lung cancer in Japanese subjects: 769 lung cancer cases and 939 non-cancer controls were included. Associations were evaluated using logistic regression models with adjustment for potential confounders (age, sex, and lifestyle factors including smoking, drinking, and green-yellow vegetable intake). We found five polymorphisms in the MT-1 gene region that showed statistically significant associations with lung cancer. Of these polymorphisms, rs7196890 showed the strongest association (odds ratio: 1.30, P = 0.004, 95% confidence interval: 1.09-1.55). The impact of the polymorphism decreased with increase of smoking, and virtually no association with lung cancer was observed among heavy smokers whose pack-year values were 30 or more (odds ratio: 1.02, P = 0.93, 95% confidence interval: 0.67-1.55). These results suggest that polymorphisms in the MT gene are moderately associated with the risk of lung cancer and that the associations are modified by lifestyle factors. *1Department of Epidemiology, Nagoya University Graduate School of Medicine *2Social Systems Research Laboratory, Toyota Central R&D Labs., Inc. *3Environmental & Applied Biotechnology Laboratory, Toyota Central R&D Labs., Inc..

*4Center for Genomic Medicine, Kyoto University Graduate School of Medicine and Faculty of Medical Sciences. *5Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences. 2.2. Polymorphisms in CYP19A1, HSD17B1 and HSD17B2 genes and serum sex hormone levels among postmenopausal Japanese women Hosono, S., Ito, H., Oze, I., Higaki, Y.*1, Morita, E.*2, 3, Takashima, N.*4, Suzuki, S.*5, Shimatani, K.*6, Mikami, H.*7, Ohnaka, K.*8, Ozaki, E.*9, Katsuura-Kamano, S.*10, Kubo, M.*11, Nagata, C.*12, Naito, M.*2, Hamajima, N.*13, Tanaka, H., and for the Japan Multi-Institutional Collaborative Cohort (J-MICC) Study Group. Extraovarian sex hormone production plays an important role in estrogen biosynthesis in postmenopausal women. We examined possible associations between serum sex hormone level and polymorphisms in CYP19A1, HSD17B1, and HSD17B2. We also assessed possible interaction between these polymorphisms and current overweight in a cross-sectional study. A total of 785 Japanese naturally postmenopausal women were randomly selected from the Japan Multi-Institutional Collaborative Cohort (J-MICC) study database. Information on lifestyle factors was obtained from a self-administered questionnaire. Serum estrogens and androgens levels were measured by liquid chromatography–tandem mass spectrometry. Four tag SNPs (single nucleotide polymorphisms) of CYP19A1, one missense SNP of HSD17B1 and three tag SNPs of HSD17B2 were examined by Invader assay. A trend test was conducted using linear regression. After adjustment for multiple comparisons, we found that rs4441215 and rs936306 in CYP19A1 and rs4888202 and rs2955160 in HSD17B2 were associated with differences in serum estrone level. Further, rs4441215 and rs936306 were associated with

Fig. 1. Trends in the prevalence of Helicobacter pylori (H. pylori) infection (a) and proportion of high-risk individuals for gastric cancer (b). These trends were characterized by the three-birth-year moving-average method with Joinpoint Regression Analysis. The resulting trend segments, as delimited in time by joinpoints, were described by birth-year percent change (BPC).

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differences in serum estradiol level. None of these polymorphisms showed any significant interaction with current body mass index (BMI). Our findings suggest that CYP19A1 and HSD17B2 polymorphisms might be associated with circulating sex hormone levels in Japanese postmenopausal women, independent of current BMI. *1Laboratory of Exercise Physiology, Faculty of Sports and Health Science *2Department of Preventive Medicine, Nagoya University Graduate School of Medicine *3Forestry and Forest Products Research Institute *4Department of Health Science, Shiga University of Medical Science *5Department of Public Health, Nagoya City University Graduate School of Medical Sciences *6Department of International Islands and Community Medicine, Kagoshima University Graduate School of Medical and Dental Science *7Division of Cancer Registry, Prevention and Epidemiology, Chiba Cancer Center Research Institute *8Department of Geriatric Medicine, Kyushu University Graduate School of Medical Sciences

*9Department of Epidemiology for Community Health and Medicine, Kyoto Prefectural University of Medicine *10Department of Preventive Medicine, Institute of Health Biosciences, The University of Tokushima Graduate School *11Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, *12Department of Epidemiology and Preventive Medicine, Gifu University Graduate School of Medicine *13Department of Healthcare Administration, Nagoya University Graduate School of Medicine 2.3. Comparison of circulating miRNA levels between gastric cancer patients and non-cancer controls Oze, I., Nagasaki, H.*1, Shimada, S.*1, Akiyama, Y.*1, Hosono, S., Ito, H., Watanabe, M., Yatabe, Y.*2, Tanaka, H., Matsuo, K.*3, Yuasa, Y.*1 Diffuse-type gastric cancer (DGC) exhibits a poor prognosis and there are no effective serum biomarkers for early detection. Shimada et al. have established an E-cadherin/p53 double conditional knockout (DCKO) mouse line, which recapitulates human DGC morphologically and molecularly. We

Genedb SNP rs

numberNumber(n=785)

MAFEstrone

a, b [mean±SD

(95%CI)] (pg/ml)Estradiol

a , c [mean±SD

(95%CI)] (pg/ml)

CYP19A1 Rs4441215 0.371CC 317 15.3±0.8 (15.3-15.4) 2.94±0.36 (2.90-2.98)CG 353 14.3±0.8 (14.2-14.4) 2.54±0.40 (2.50-2.59)GG 115 13.4±0.8 (13.2-13.5) 2.18±0.36 (2.11-2.25)

trend P -valued

0.003*

<0.001*

CYP19A1 Rs936306 0.402CC 286 13.7±0.8 (13.6-13.8) 2.32±0.38 (2.27-2.36)CT 367 14.8±0.9 (14.7-14.9) 2.75±0.38 (2.71-2.79)TT 132 15.9±0.8 (15.7-16.0) 3.12±0.37 (3.05-3.18)

trend P -valued

0.001*

<0.001*

HSD17B2 Rs4888202 0.478CC 204 15.6±0.8 (15.5-15.7) 2.67±0.39 (2.62-2.73)CT 412 14.5±0.7 (14.5-14.6) 2.65±0.38 (2.61-2.69)TT 169 13.5±0.7 (13.4-13.6) 2.63±0.39 (2.56-2.69)

trend P -valued

0.004* 0.863

HSD17B2 Rs2955160 0.382

GG 294 15.3±0.8 (15.2-15.4) 2.61±0.37 (2.56-2.65)

GC 382 14.4±0.7 (14.3-14.5) 2.67±0.39 (2.63-2.72)CC 109 13.4±0.8 (13.2-13.6) 2.70±0.41 (2.62-2.78)

trend P -valued

0.008* 0.368

aMultivariate models adjusted for age, postmenopausal period, current BMI, smoking, alcohol consumption, regular exercise,history of any hormone therapy and SHBG level.b31 subjects were excluded due to outlier (estrone>31.6pg/ml).

c40 subjects were excluded due to outlier (estradiol>8.3pg/ml).

dLinear regression model

*Significant P -value after adjusting multiple comparison by Holm procedure

Abbreviations: MAF, minor allele frequency

Table 1. Multivariate-adjusted means of sex steroid hormone levels

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identified three circulating miRNAs (miR-103, miR-107, miR-194) as biomarkers of detecting early DGC using this DCKO mouse model. The purpose of this study was to evaluate the usefulness of the circulating miRNAs for the detection of human DGC. Subjects were first-visit outpatients at Aichi Cancer Center Hospital. Cases were 50 patients with DGC. Controls were age and sex matched non-cancer outpatients. Lifestyle information was collected by self-administered questionnaire. Total RNA was extracted from the plasma samples with miRNeasy Serum/Plasma Kit, and then reverse-transcribed using an miScript II RT Kit. The levels of miRNAs in plasma samples were determined using an miScript SYBR Green Kit. Spiked-in cel-miR-39 was analysed as a normalisation control.The three miRNA levels were not correlated with any clinical factors. The area under the ROC curve (AUC) of miR-103, miR-107, miR-194 and the combination of three miRNAs were 0.55, 0.56, 0.51 and 0.62, respectively. The mean miRNA levels were not different between cases and controls. Thus plasma miR-103, miR-107 and miR-194 levels do not appear to be useful biomarkers for detecting DGC. *1Department of Molecular Oncology, Tokyo Medical and Dental University *2Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital *3Division of Molecular Medicine, Aichi Cancer Center Research Institute 3. Tobacco control 3.1. Factors associated with successful and maintained quit smoking status among patients who received Japanese smoking cessation therapy Tanaka, H., Taniguchi, C.*1, Saka, H.*2, Oze, I., Tachibana, K.*3, Nozaki, Y.*4, Suzuki, Y.*5, Suehisa, H.*6, Sakakibara, H.*7 Objectives: Although nine years have passed since the start of the Japanese smoking cessation therapy (SCT) program, few studies have investigated cognitive and psychological factors associated with the success of quitting smoking. The aim of this study was to identify factors associated with the success of quitting smoking in the SCT and 12 months’ maintained cessation among abstainers in the SCT. Methods: In a multi-institutional study at six smoking cessation clinics, we performed multivariate logistic regression analysis for 660 participants using the following independent variables: age, sex, having present illness, cohabiter,

cohabitant with smoker, age at smoking initiation, motivation to quit smoking, self-efficacy of quitting smoking, the Center for Epidemiologic Studies depression scale (CES-D), the Fagerström test for nicotine dependence (FTND), strength of desire to quit, previous abstinence, and varenicline use. Analysis of factors associated with maintained cessation, which was defined as successful cessation at 3, 6 and 12 months after the SCT, in the 550 abstainers at the end of SCT was subsequently performed. Results: Having higher self-efficacy of quitting smoking (OR: 1.39, 95%CI: 1.06-1.82) and varenicline use (OR: 2.48, 95% CI: 1.23-5.03) were associated with success of the SCT. Strong desire to smoke (OR: 0.67, 95%CI: 0.52-0.88) was a risk factor for obstructing maintained cessation during the 12 months after the end of SCT. Conclusion: Assessment of self-efficacy and strength of desire to smoke is important for Japanese SCT participants. *1Department of Nursing, Sugiyama Jogakuen University *2Department of Respiratory Medicine, National Hospital Organization Nagoya Medical Center *3Department of Respiratory Medicine, National Hospital Organization Kinki-Chuo Chest Medical Center *4Department of Respiratory Medicine, Japan Community Healthcare Organization Chukyo Hospital *5Department of Respiratory Medicine, Kitasato University Kitasato Institute Hospital *6Department of Chest Surgery, National Hospital Orgnaization Iwakuni Medical Center *7Department of Nursing, Nagoya University Graduate School of Medicine

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From front to back

Left row: Dr. H. Iioka, Ms. Y. Ito, Ms. R. Watanabe Right row: Mr. T. Sato, Ms. Niwa, Dr. K. Saito, Dr. E. Kondo, Ms. M. Tanaka

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Division of Oncological Pathology ________________________________________________________________________________

Eisaku Kondo, M.D., PhD. Chief Hayao Nakanishi, M.D., PhD., Section Head (until Dec. 2013) Ken Saito, PhD. Senior Researcher (as of April 2013) Keiko Shinjo, M.D., Ph.D. Senior Researcher (as of April 2012) Susumu Nakata, M.D. Ph.D. Senior Researcher (as of April 2011) Daisuke Yamashita, M.D., Research Resident (as of 2013) Hideaki Ito, M.D., Research Resident (as of April 2014) Takuya Saito, M.D., Graduate course student (as of April 2012) Risayo Watanabe. Research Assistant (as of Feb 2013) Noriko Saito. Research Assistant Yumiko Ito. Research Assistant (as of April 2012) Tomoaki Sato. Research Assistant (as of April 2012) Visiting Scientist Hidekazu Iioka. M.D., PhD. Aichi Medical University Akiko Yusa. Nagoya University Faculty of Engineering Visiting Trainees Mizuna Tanaka. Meijoh University Faculty of Pharmacy Kohki Murakami. Nagoya University Graduate School of Medicine. Tomomi Furuya. Meijoh University Faculty of Pharmacy Kayoko Terasawa. Meijoh University Faculty of Pharmacy

General Summary

The aim for our research at the Division of Oncological Pathology is to disclose the pathogenesis of human malignancies, especially focusing on intractable tumors such as advanced stage cancers of the gastrointestinal tract, including examples in the oral cavity and other head and neck sites, lung cancers, brain tumors, aggressive leukemias and so on, through molecular analyses based on data obtained by morphological and biological examination of cancer tissues and human cancer cells. Our interest is now concretely focused on finding novel therapeutic targets through basic pathological research and molecular analysis of progression, metastasis, invasion, and stem cell pathology. As a second important aim, we are also making efforts to develop advanced antitumor medical technologies for clinical application. In addition to these molecular pathological research activities, another important responsibility of our division is an autopsy service, which provides a basis for understanding of neoplasia with implications inmmay areas and providing motivation for new research activity. Postmortem examinations allow valuable information to be obtained on the behavior of neoplasms and their response to therapy, helping clarify pathogenesis. Thus, the present aim of our division is to promote comprehensive pathological research and contribute to current and near-future tumor medicine. 1. Coxsackie and adenovirus receptor – a novel negative regulator of RhoA associated kinase (ROCK) - is a critical regulator of survival and growth of oral squamous carcinoma cells Saito, K., Sakaguchi, M.*1, Iioka, H., Matsui, M., Nakanishi, H., Huh N.*1 and Kondo, E.

The Coxsackie and adenovirus receptor (CAR) is essential for adenovirus infection of target cells. Constitutive expression in various cancer and normal tissues has been reported and recently the biological role of CAR in human neoplasms of

several different origins has been investigated with respect to tumor genesis, progression and metastasis. However, its biological functions in tumor cells remain controversial. We established a critical role of CAR in growth regulation of oral squamous cell carcinomas (SCCs) in vitro and in vivo via specific interaction with Rho-associated protein kinase (ROCK). In particular, loss of endogenous CAR expression by knockdown using a specific siRNA facilitates growth suppression of SCC cells due to cell dissociation, followed by apoptosis. The

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consequent morphological reaction appears reminiscent of anoikis, rather than the epithelial-mesenchymal transition (EMT), and the dissociation of oral SCC cells appears to be triggered not by lack of contact with extracellular matrix (ECM), but by loss of cell-to-cell contact caused by abnormal translocation of E-cadherin from surface membranes to cytoplasm. Immunoprecipitation assays of the CAR-transfected oral SCC cell line, HSC-2, with or without ROCK inhibitor (Y-27632), revealed that CAR directly associates with ROCKI and ROCKII, resulting in inhibition of ROCK activity and contributing to maintenance of cell-to-cell adhesion for growth and survival. Based on these findings, in vivo behavior of CAR-downregulated HSC-2 cells from siRNA knockdown was compared with that of normally CAR-expressing cells in intraperitoneally xenografted mouse models. We found that mice engrafted with CAR siRNA-pretreated HSC-2 cells showed poor formation of metastatic foci in contrast to those implanted with control siRNA-pretreated cells that maintained endogenous CAR expression and that disseminated extensive peritoneal lesions. Thus, CAR substantially impacts on growth and survival of oral SCC cells through specific interactions with ROCK in vitro and in vivo, providing clues for the molecular therapy or head and neck SCCs. *1 Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences,

Okayama University 2. A extract of Cordyceps militaris inhibits angiogenesis and suppresses tumor growth of human malignant melanoma cells Ruma IMW*1, Putranto EW*1, Kondo E, Watanabe R, Saito K, Inoue Y, Yamamoto K, Nakata S, Kaihata M, Murata H and Sakaguchi M*1.

Angiogenesis is essential for tumor development and metastasis. Among several angiogenic factors, vascular endothelial growth factor receptor (VEGF) is important for tumor angiogenesis and is commonly overexpressed in solid tumors. Thus, many antitumor strategies targeting VEGF have been developed to inhibit cancer angiogenesis, offering hope successful treatment of solid cancers. However, there are a number of issues such as harmful effects on normal vascularity in clinical trials. Taking this into consideration, we employed Cordyceps militaris as an antitumor approach due to its biological safety in vivo. The herbal medicinal mushroom Cordyceps militaris has been reported to show potential anticancer properties including anti-angiogenic capacity; however, its concrete properties have yet to be fully demonstrated. In this study, we aimed to elucidate the biological role of Cordyceps militaris extract in tumor cells, especially in regulating angiogenesis and growth of a human malignant melanoma cell line. We demonstrated the Cordyceps militaris extract to remarkably suppress tumor growth via induction of apoptotic cell death in culture, linked to abrogation of VEGF production in melanoma cells. This was followed by mitigation of Akt1 and GSK-3β activation, while p38α phosphorylation levels were increased. Extract treatment in a mouse model xenografted with human melanoma cells resulted in a dramatic antitumor effect with down-regulation of VEGF expression. The results suggest that suppression of tumor growth by Cordyceps militaris extract is, at least, mediated by its anti-angiogenicity and apoptosis induction capacities. Cordyceps militaris extract may be a potent antitumor herbal drug for solid tumors.

*1 Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University *2 Division of Cancer Biology, The Cancer Institute of the Japanese Foundation for Cancer Research (JFCR) *3 Department of Tumor Immunology, Aichi Medical University School of Medicine *4 Department of Respiratory Medicine, Okayama University Hospital

Fig. 1. Schematic representation of biological effects of CAR (Coksackie and adenovirus receptor) on Rho A-associated kinase. Moderate suppression of ROCK activity by CAR facilitates growth, invasion and metastasis of SCC cells. This work was published in “Oncogene” March 18, 2013.

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3. Development of a New Rapid Isolation Device for Circulating Tumor Cells (CTCs) using 3D Palladium Filter and its Application for Genetic Analysis Yusa A, Toneri T, Masuda T, Ito S, Yamamoto S, Okochi M, Kondo N, Iwata H, Yatabe Y, Ichinosawa Y, Kinuta S, Kondo E, Honda H, Arai F, Nakanishi H.

Circulating tumor cells (CTCs) in the blood of patients with epithelial malignancies provide a promising and minimally invasive source for early detection of metastasis, monitoring of therapeutic effects and basic research addressing the mechanisms of metastasis. In this study, we developed a new filtration-based, sensitive CTC isolation device, consisting of a 3-dimensional (3D) palladium (Pd) filter with an 8 μm-sized pore in the lower layer and a 30 μm-sized pocket in the upper layer to trap CTCs on a filter micro-fabricated by precise lithography plus electroforming processes. This simple pump-less device driven by gravity flow can enrich CTCs from whole blood within 20 min. After on-device staining of CTCs for 30 min, the filter cassette was removed from the device, fixed in a cassette holder and set up on an upright fluorescence microscope. Enumeration and isolation of CTCs for subsequent genetic analysis were completed within 1.5 hr and 2 hr, respectively. Cell spike experiments demonstrated that the

recovery rate of tumor cells from blood with this Pd filter device was more than 85%. Single living tumor cells were efficiently isolated from spiked tumor cells by a micromanipulator, and KRAS mutation, HER2 gene amplification and overexpression, for example, were successfully detected from such isolated single tumor cells. Sequential analysis of blood from mice bearing metastases revealed that CTC increased with progression of metastasis. Furthermore, a significant increase in the number of CTCs from the blood of patients with metastatic breast cancer was observed compared with patients without metastasis and healthy volunteers. These results suggest that this new 3D Pd filter-based device could be a useful tool for rapid, cost effective and sensitive detection, enumeration, isolation and genetic analysis of CTCs from peripheral blood in both preclinical and clinical settings.

Fig. 2. Treatment with C. militaris extract reduced growth of subcutaneously xenografted melanomas. (A) Gross appearance of xenografted tumors. Tumors with subcutaneous melanoma tissues were excised from mice after 37 days with or without C. militaris extract treatment. Compared to the control group, C. militaris -treated mice showed small tumors. (B) Histology (H&E staining) and immunohistochemistry of excised tumors of mice treated with C. militaris or saline (control). Expression of VEGF on tumor cells and morphology of vascular vessels in tumor tissues stained by CD31 mAb are shown. Both VEGF and CD31 expression were reduced in C. militaris-treated tumors. (C) Growth of subcutaneously xenografted melanomas in mice after treatment with C. militaris or saline. Mice bearing subcutaneous MeWo xenografts were treated with saline or the supernatant of C. militaris after tumor volumes had reached ∼ 100

mm3 (day 1). Tumor-bearing mice in each group were subjected to subcutaneous administration of the supernatant or saline once every two days for 37 days consecutively. Tumor volumes were measured daily from day 1 to day 37. Statistical significance of tumor volumes and that of tumor masses were evaluated by Student’s t-tests. Saline (n=3, mean volume of 2101 mm3 on day 37) vs. C. militaris (n=3, mean volume 384 mm3 on day 37); *P=0.069 >0.05. Final masses of tumors excised on day 37 in each group are also shown in the graph (right). Saline (n=3, mean weight of 874 mg) vs. C. militaris (n=3, mean weight of 230 mg); **P=0.031 <0.05. Means and SE (standard error) of triplicates are shown.

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4. New whole-body multimodality imaging of gastric cancer peritoneal metastases combining fluorescence imaging with ICG-labeled antibodies and MRI in mice

Ito A, Ito Y, Matsushima S, Tsuchida D, Ogasawara M, Hasegawa J, Misawa K, Kondo E, Kaneda N, Nakanishi H.

Peritoneal metastasis is the most frequent pattern of recurrence after curative surgery for gastric cancer. However, such recurrence is difficult to detect by conventional computed tomography (CT) and magnetic resonance imaging (MRI) at an early stage. To improve the sensitivity and specificity of diagnostic imaging for peritoneal metastases, here, we developed a new type of multimodality imaging combining fluorescence with near-infrared fluorophore (NIR)-labeled antibodies and MRI. Dual optical imaging of peritoneal metastases was carried out using luciferase-tagged gastric cancer cell lines and XenoLight CF750 or indocyanine-green (ICG)-labeled anti-human EGFR or CEA antibodies as probes in mice with an Ivis in vivo imaging system. This whole-body fluorescent imaging system sensitively and noninvasively detected metastatic foci less than 1mm in diameter in the peritoneal cavity. Fluorescence imaging proved to be specific because fluorescence signals were abolished by blocking with an excess amount of unlabeled antibody. Although this fluorescence imaging had higher sensitivity for detection of small-sized peritoneal metastases than MRI, it

proved difficult to accurately determine the organ distribution of metastases. We thus developed a multimodality imaging system by fusion of 3 dimensional (3D) fluorescence with MRI imaging and demonstrated improved diagnostic accuracy over either method alone.

The present results suggest that multimodality imaging consisting of fluorescence imaging with NIR-labeled EGFR or CEA antibodies and MRI allows sensitive, specific and anatomically accurate detection of peritoneal metastases at an early stage, noninvasively.

Fig. 3. Detection and enumeration of CTC from patients with breast cancers. A-D Representative CTC cluster showing a EpCAM+/CD45-/Hoechst33342+ pattern. This work was published in PLOS ONE 11;9(2):e88821. 2014.

Fig. 4. Multimodality imaging with combination of 3D optical imaging and MRI for peritoneal metastases. Multimodality images constructed by fusion of optical and MRI images. This work was publicshed in Gastric Cancer 173(3), 497-507. 2014

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From left to right First row: Ms. Yuri Nishimura, Ms. Yumiko Suyama, Ms. Anna Ogiso, Dr. Yoshitaka Sekido, Ms. Haruna Ikeda, Dr. Yuko Murakami-Tonami, Ms. Miwako Nishizawa Second row: Mr. Yoshio Tatematsu, Dr. Kosuke Tanaka, Dr. Akihiro Matsushita, Dr. Taketo Kato, Dr. Hirotaka Osada, Ms. Yumi Nakahama Inset: Dr. Hiromi Furuta

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Division of Molecular Oncology ________________________________________________________________________________

Yoshitaka Sekido M.D., Ph.D., Chief Hirotaka Osada, M.D., Ph.D., Section Head Yutaka Kondo, M.D., Ph.D., Section Head (until April 2014) Makiko Fujii, D.D.S., Ph.D., Senior Researcher (until August 2015) Yuko Murakami-Tonami, M.D., Ph.D., Senior Researcher Yoshio Tatematsu, B.S., Research Assistant Miwako Nishizawa, B.P., Research Assistant Haruna Ikeda, Semi-regular Employee (as of April 2014) Yumi Nakahama, Semi-regular Employee Research Resident Fumiharu Ohka, M.D., Nagoya University Graduate School of Medicine (until June 2014) Shuhei Hakiri, M.D., Nagoya University Graduate School of Medicine (until March 2015) Akihiro Matsushita, M.D., Nagoya University Graduate School of Medicine (as of July 2014) Taketo Kato, M.D., Nagoya University Graduate School of Medicine (as of April 2015) Visiting Trainees Hiromi Furuta, M.D., Nagoya City University Graduate School of Medicine Akihiro Matsushita, M.D., Nagoya University Graduate School of Medicine (until June 2014) Taketo Kato, M.D., Nagoya University Graduate School of Medicine (until March 2015) Kosuke Tanaka, M.D., Nagoya University Graduate School of Medicine (as of April 2014) Maiko Yoshida, M.D, Nagoya University Graduate School of Medicine (as of April 2015) Eri Ikeda, Meijo University (until August 2015) Anna Ogiso, Meijo University (as of August 2014) Arisu Nimura, Kinjo Gakuin University (May~July 2014) Mao Inayoshi, Kinjo Gakuin University (May~July 2014) Yuri Nishimura, Kinjo Gakuin University (as of December 2015) Yumiko Suyama, Kinjo Gakuin University (as of December 2015)

General Summary

Our goal is to determine genetic lesions and epigenetic alterations giving rise to human solid cancers and use this information for prevention, diagnosis, and treatment of these diseases. Currently, we are focusing on malignant mesothelioma and lung cancer. These studies also provide an opportunity to dissect biochemical and pathological pathways of malignant phenotypes including deregulated cell proliferation, invasion, metastasis and drug resistance. Human cancers arise because of genetic mutations in oncogenes and tumor suppressor genes, and we are approaching the problem by study of candidate genes, systematic molecular analysis of biochemical pathways, and global approaches such as microarray analysis of gene expression profiles and next generation sequencing. Epigenetic changes featuring DNA methylation, histone modification, and microRNA expression have also been identified not only as mechanisms of inactivation of tumor suppressor genes but also as fundamental for regulated maintenance of cancer stem cell populations and differentiated cell lineages in each tissue. We also functionally analyze candidate genes by transducing wild type copies into human cancer cells and testing for their ability to suppress malignancy in vitro and in vivo as well as characterizing their protein products biochemically. Alternatively, we inactivate their expression using RNA interference (RNAi) in either tumor or normal cells and then study the resultant phenotype. Understanding the functions of the genes mutated and the signaling pathways disrupted should provide a foundation for a translational research approach to human malignancies, from bench to bedside.

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1. Functional differences between wild-type and mutant-type BAP1 tumor suppressor against malignant mesothelioma cells Hakiri, S., Osada, H., Ishiguro, F., Murakami, H., Murakami-Tonami, Y., Yokoi, K.*1, and Sekido, Y.

Malignant mesothelioma (MM) is an aggressive neoplasm which is developed from the pleural or peritoneal cavities. The BRCA1-associated protein 1 (BAP1) gene, which is located on chromosomal 3p21.1, has been shown to be frequently inactivated in MM. BAP1 encodes a nuclear-localized deubiquitinating enzyme with an NH2-terminal ubiquitin COOH-terminal hydrolase domain and a COOH-terminal domain which contains two nuclear localization signals (Fig 1a).

Among the 19 cell lines that we established from Japanese MM patients, we found BAP1 mutations in 5 cell lines (Fig 1a). To clarify the inactivation mechanisms of the BAP1 mutants, we first studied the subcellular localization of BAP1. We demonstrated that the wild-type preferentially resides in the nucleus of the cells but the mutant BAP1 is excluded from the nucleus (Fig 2b). Transduction of the wild-type BAP1 vector induced both inhibition of cell proliferation and anchorage-independent cell growth of MM cells with BAP1-deletion, while BAP1 mutants of a missense or C-terminal truncated form showed only partial or no growth inhibitory effects. Next, we studied whether or not BAP1 is involved in MM cell survival after DNA damage. After irradiation (IR), we detected that both wild-type and mutant BAP1 were similarly phosphorylated and phospho-BAP1 was localized mainly in the nucleus. Interestingly, BRCA1 proteins were decreased in the MM cells with BAP1 deletion, and that transduction of the mutants as well as wild-type BAP1 increased BRCA1 proteins, suggesting that BAP1 may promote DNA repair partly through the stabilization of BRCA1 protein. Additionally, using the MM cells with BAP1 deletion, we found that the wild-type, and even a missense mutant, BAP1 conferred a higher survival rate after IR compared to the control vector. Our results indicated that, while wild-type BAP1 suppresses MM cell proliferation and restores cell survival after IR-damage, some mutant BAP1 may also moderately retain these functions. *1Department of Thoracic Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan

2. SMC2 regulates the transcription of DDR genes and shows synergistic phenotype with MYCN Murakami-Tonami, Y., Kishida, S.*1, Takeuchi, I.*2, Katou, Y.*3, Maris, JM.*4, Ichikawa, H.*5, Kondo, Y.*6, Sekido, Y., Shirahige, K.*3, Murakami, H.*7, and Kadomatsu, K.*1 The condensin complex is required for chromosome condensation during mitosis. It has been reported that condensin complex also has a role in interphase, but it is still not clear about its role in interphase compared to mitosis. Neuroblastoma is the most common extracranial childhood tumor of sympathetic neuron. In human neuroblastoma, MYCN amplification correlates with poor prognosis. Here we found that downregulation of SMC2 (structural maintenance of chromosome 2), condensin complex subunit, and MYCN amplification/overexpression showed synergistic

Fig. 1. (a) BAP1 gene mutations in MM cell lines. The five cell lines (Y-MESO-9, 14, 25, and 61, and ACC-MESO-4) were established in our lab, and two (NCI-H28 and H2452) were kindly provided from Dr. Adi F. Gazdar. (b) BAP1 mutation effects on its own nuclear localization. Immunofluorescence analysis of subcellular BAP1 localization was performed after transduction of BAP1 vectors, and percentages of subcellular localization of BAP1 were calculated.

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lethal response in human neuroblastoma cells. SMC2 knockdown in MYCN amplified/overexpressed neuroblastoma cells induced DNA damage, leading to apoptosis. In addition, we showed that SMC2 interacts MYCN and transcriptionally regulates DNA damage response (DDR) genes. Finally we showed that patients bearing MYCN amplified tumors tend to benefit from low SMC2 expression. Our results identify novel function of SMC2 (or condensin complex) in DDR and we proposed that SMC2 or condensin complex is a potential molecular target of MYCN-amplified neuroblastoma.

*1Department of Molecular biology, Nagoya University Graduate School of Medicine *2Department of Computer Science/Scientific and Engineering Simulation, Nagoya Institute of Technology *3Laboratory of Genome Structure & Function, Institute of Molecular and Cellular Biosciences, The University of Tokyo *4Department of Pediatrics and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, University of Pennsylvania *5Division of Genetics, National Cancer Institute *6Department of Epigenomics, Nagoya City University Graduate School of Medical Sciences *7Department of Biological Science, Faculty of Science and Engineering, Chuo University

Fig. 2. (a) Knockdown of SMC2 induces DNA damage and apoptosis. Growth of MYCN-overexpressed SH-EP cells and control SH-EP cells infected with non-target shRNA or SMC2-specific shRNAs. Counting started 3 days after infection. On each day, three plates were counted and averaged. Data are shown as a ratio of the number of cells at 3 days after transfection and are represented as the mean ± SD of n = 3 independent repeats. (b) SMC2 knockdown efficiency of (a). (c) The effects of SMC4 (condensin subunit) expression on the overall survival (OS) and event-free survival (EFS) rates of patients bearing MYCN high-expression and low-expression tumors. Within each of the two tumor subsets considered, those with expression levels of each condensin subunit greater than the median (blue or green line) were compared to the remainder of the tumors in the subset (red or purple line) using a Kaplan-Meier analysis.

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From left to right First row: Dr. M. Katayama, Ms. K. Hirano, Ms. Y. Kasugai, Dr. K. Matsuo, Dr. S. Tsuzuki, Dr. T. Kakiuchi, Ms. I. Morikawa. Second row: Dr. M. Sawabe, Dr. T. Ugai, Dr. H. Masaoka, Dr. T. Takahara, Ms. S. Sato.

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Division of Molecular Medicine ________________________________________________________________________________

Keitaro Matsuo, M.D., Ph.D., M.Sc. Chief Shinobu Tsuzuki, M.D., Ph.D. Section Head Miyuki Katayama, M.D., Ph.D. Senior Researcher Yumiko Kasugai, B.S. Research Assistant Taishi Takahara, M.D. Research Resident Hiroyuki Masaoka, M.D. Research Resident Kyoko Hirano, B.S. Research Assistant Visiting Trainees Noriaki Yoshida, M.D. Nagoya University Graduate School of Medicine (until June 2014) Tatsuo Kakiuchi, M.D. Nagoya University Graduate School of Medicine Tomotaka Ugai, M.D. Jichi Medical University Graduate School of Medicine Michi Sawabe, M.D. Nagoya City University Graduate School of Medicine

General Summary

Research in this laboratory is focused on elucidating genetic and molecular bases of human cancer acting in conjunction with environmental exposures, with a view to applying the obtained knowledge to clinical oncology and prevention. Currently we are working on two aspects with physicians/researchers within and outside Aichi Cancer Center, : 1) molecular epidemiology of cancer and it’s applications in clinical oncology and prevention,; and 2) molecular biology on of hematological malignancies, with physicians/researchers within and outside Aichi Cancer Center. Sporadic cancers are consequences of molecular/genetic events after environmental exposure and it’s combinationinteracting with the genetic background. Elucidating optimal combinations of environmental and genetic factors is essential for targeted prevention and treatment. In collaboration with the Division of Epidemiology and Prevention, we are trying to: (1) elucidate new gene-environment interactions ;between genetic background and environmental factors, (2) development of risk prediction models integrating genetic and environment factors, ; and (3) development of applications of developed models in both pre- and post-clinical settings. Hematological malignancies are highly associated with genetic changes so that some hematological malignanciesexamples can be classified according to genetic changes specific to given disease entities. Such close associations provides evidence that the genetic changes play pivotal roles in disease development and/or clinicopathological manifestations. Over the last two years, we have studied several issues in particular: (1) elucidation of combinatorial combination effects of genes involved in lymphomagenesis using a newly established mouse lymphoma model; (2) establishment of a method to generate ATL-like neoplasms in mice employing in vitro-induced T cells; (3) involvement of clonal heterogeneity in the development of lymphoma and its impact on clinical outcome; (4) establishment of a model of YAP-driven malignant mesothelioma. 1. Establishing prediction models of upper-aerodigestive tract cancer using molecular and environmental information Koyanagi, Y.*1, Ito, H.*2, Oze, I.*2, Hosono, S.*2, Watanabe, M.*2, Tanaka, H.*2, Abe, T.*3, Shimizu, Y.*3, Hasegawa, Y.*4, and Matsuo, K.

Alcohol consumption and aldehyde dehydrogenase 2 (ALDH2) polymorphisms are associated with upper-aerodigestive tract (UATC) risk, and a significant gene-environment interaction between the two has been confirmed in various studies in Asia. We have developed a risk prediction model and estimated absolute risks

stratified by a combination of ALDH2 genotype and alcohol consumption to aid the development of personalized prevention. We conducted two age- and sex- matched case-control studies, one (630 cases and 1,260 controls) for model derivation and the second (654 cases and 654 controls) for external validation. Based on data from the derivation study, a prediction model was developed by fitting a conditional logistic regression model using the following predictors: age, sex, smoking, drinking, and ALDH2 genotype. The risk model, including a combination of ALDH2 genotype and alcohol consumption, provided high discriminatory

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accuracy and good calibration in both the derivation and validation studies: C statistics were 0.82 (95% confidence intervals 0.80–0.84) and 0.83 (0.81–0.85), respectively, and calibration plots of both studies stayed close to the ideal calibration line. Cumulative risks were obtained by combining odds ratios estimated from the risk model with the age-specific incidence rate and population size. For heavy drinkers with a heterozygous genotype, cumulative risk at age 80 was above 20%. In contrast, risk in the other groups was less than 5%. In conclusion, modification of alcohol consumption according to ALDH2 genotype will have a major impact on UATC prevention. These findings represent a simple and practical model for personalized cancer prevention.

*1Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences, Fukuoka, Japan *2Division of Epidemiology and Prevention, Aichi Cancer Center Research Institute, Aichi, Japan *3Department of Gastrointestinal Surgery, Aichi Cancer Center Central Hospital, Aichi, Japan *4Department of Head and Neck Surgery, Aichi Cancer Center Central Hospital, Aichi, Japan Division of Molecular Medicine

2. Generation of mouse models of lymphoid neoplasms using retroviral gene transduction of in vitro-induced germinal center B cells Takahara T., Arita, K.*1, Yoshida, N.*2, Sugiyama, T.*1, Seto, M.*2, and Tsuzuki, S. Evidence is accumulating that hematologic malignancies develop following acquisition of multiple genetic changes. Because of the complexity of these genetic changes, the generation of animal models is often laborious. In an effort to circumvent this difficulty, we previously established a mouse model by employing in vitro-induced mouse germinal center (GC) B cells; the GC B cells were induced in vitro, retrovirally transduced with a combination of genes or mutated genes of interest, and transplanted into mice. Using this model system, we were able to generate diffuse large B cell lymphoma (DLBCL) by a combination of Myc and Bcl2. We also found that a combination of Burkitt lymphoma-associated genes Myc, CCND3T283A, E47V557E, Akt and TCL1A induced Burkitt-like lymphoma, and that a combination of Card11L232LI and Bcl6 induced DLBCL in mice. All mice receiving a transplant of Card11L232LI/Bcl6 co-transduced GC B cells died or developed lymphoma within two months after transplantation, while none of a group of mice receiving a transplant of GC B cells

singly-transduced with either Card11L232LI or Bcl6 died during the same period of time. The developed lymphomas expressed exogenously expressed Card11L232LI and Bcl6, and endogenous Irf4, which is a molecular hallmark of activated B cell-like DLBCL, the most aggressive subtype of DLBCL. These mouse models may help elucidate the molecular mechanisms underlying B cell neoplasms and may aid in the development of effective therapeutic drugs. *1Third Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan *2Department of Pathology, School of Medicine, Kurume University, Kurume, Japan

3. Establishment of a new mouse model of adult T cell leukemia Kasugai-Maeda, Y., Yoshida, N.*1, Seto, M.*1, and Tsuzuki, S.

Acute type adult T-cell leukemia (acute ATL) develops in human T-cell leukemia virus type 1 (HTLV-1) carriers. Although the HTLV-1-encoded HBZ gene is critically involved, HBZ alone is insufficient, and cooperative additional “hits” are required for the development of ATL. Candidate cooperative hits are being delineated, but methods to rapidly explore their roles in ATL development in collaboration with HBZ are lacking. We present a new mouse model of rapidly generated acute ATL that features transplanting in vitro-induced T cells retrovirally transduced with HBZ, and two cooperative genes BCLxL and AKT, into mice. T cells co-transduced with HBZ/BCLxL/AKT allowed in vitro-generated T cells to grow in the absence of cytokines (Flt3-ligand and IL-7), which was not attainable with the use of any combination of the two genes. Upon transplantation into mice, although transplanted T cells were a mixture of cells variously transduced with the three genes, the tumors developing in the animals were composed of HBZ/BCLxL/AKT-triply transduced T cells, showing synergistic activity of the three genes. The genetic/epigenetic landscape of ATL has only recently been elucidated, and actual roles of the elucidated “hits” in ATL pathogenesis remain to be explored. Our model thus is important in providing a versatile tool to explore roles of the hits in the development of acute ATL, in collaboration with HBZ.

*1Department of Pathology, School of Medicine, Kurume University, Kurume, Japan

4. Clonal heterogeneity of lymphoid

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malignancies correlates with poor prognosis Katayama, M., Yoshida, N., Umino A.*1, Kato H.*2, Tagawa, H.*3, Nakagawa, M.*4, Fukuhara, N.*5, Sivasundaram, S.*6, Takeuchi, I.*7, Hocking TD.*8, Arita, K., Karube, K., Tsuzuki. S, Nakamura, S.*9, Kinoshita T.*2, and Seto, M.

Clonal heterogeneity in lymphoid malignancies has been recently reported in adult T-cell lymphoma/leukemia, peripheral T-cell lymphoma, not otherwise specified, and mantle cell lymphoma. We have extended analyses to other types of lymphoma including marginal zone lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. To determine the presence of clonal heterogeneity, 332 cases were examined using array comparative genomic hybridization analysis. Results showed that the incidence of clonal heterogeneity varied from 25% to 69% among different types of lymphoma. Survival analysis revealed that mantle cell lymphoma and diffuse large B-cell lymphoma with clonal heterogeneity showed significantly poorer prognosis, and that clonal heterogeneity was confirmed as an independent predictor of poor prognosis for both types of lymphoma. Interestingly, 8q24.1 (MYC) gain, 9p21.3 (CDKN2A/ 2B) loss and 17p13 (TP53, ATP1B2, SAT2, SHBG) loss were recurrent genomic lesions among various types of lymphoma with clonal heterogeneity, suggesting at least in part that alterations of these genes may play a role in clonal heterogeneity.

*1Department of Hematology and Oncology, Mie University Graduate School of Medicine *2Department of Hematology and Cell Therapy, Aichi Cancer Center hospital, Nagoya, Japan; *3Department of Hematology, Nephrology, and Rheumatology, Akita University Graduate School of Medicine, Akita, Japan *4Lymphoid Malignancies Branch, Center for Cancer Research, National Cancer Institute, USA *5Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Japan *6Department of Biochemistry, Aichi Medical University School of Medicine, Nagakute, Japan *7Department of Computer Science/Scientific and Engineering Simulation, Nagoya Institute of Technology, Nagoya, Japan *8Department of Human Genetics, McGill University, Montréal, Canada; *9Department of Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan

5. Establishment of a model of YAP-driven malignant mesothelioma Kakiuchi, T., Takahara, T., Kasugai-Maeda, Y., Arita,

K.*1, Yoshida, N.*2, Karube, K.*3, Katayama, M., Nakanishi, H.*4, Kiyono, T.*5, Nakamura, S.*6, Osada, H.*7, Sekido, Y.*7, Seto, M.*2,8, and Tsuzuki, S.

Disruption of the Hippo pathway as a result of deletion and/or mutation of the involved genes (e.g., neurofibromin 2 [NF2]) is frequently observed in mesothelioma. The disruption results in reduced phosphorylation of yes-associated protein (YAP), the non-phosphorylated YAP translocating to the nucleus and regulating gene expression. While roles of the disrupted Hippo pathway in maintenance of established tumors have been investigated using mesothelioma cell lines, involvement in the initiation of mesothelioma development remains unclear.We have employed immortalized human mesothelial cells to study the transformation process, and found that NF2 knockdown led to transformation of the cells concurrently with reduction in YAP phosphorylation. The targeted cells exhibited enhanced growth in vitro, and formed tumors following transplantation into nude mice. Similar results to those obtained by NF2 knockdown were also achieved using forced expression of wild-type (wt) or constitutively active (S127A) YAP. Although such directed expression of YAPwt or YAPS127A was insufficient to transform primary (unimmortalized) human mesothelial cells, our findings provide evidence for crucial roles of activated YAP in transformation of mesothelial cells. To identify YAP-regulated genes critical for mesothelial tumorigenesis, we conducted gene expression analysis comparing control- and YAP-transduced immortalized human mesothelial cells. Gene Set Enrichment Analysis (GSEA) using a gene set down-regulated by YAP knock-down in mesothelioma cell lines revealed phospholipase C beta 4 (PLCB4) to be among the top-ranking genes up-regulated by YAP in our experiments. PLCB4 was up-regulated by YAP in immortalized human mesothelial cells, and down-regulated by YAP knock-down in YAP-driven mesothelioma cells. shRNA-mediated silencing of PLCB4 attenuated the growth of YAP-transduced mesothelial cells and Hippo-disrupted, but not -proficient, mesothelioma cell lines.

Our model system thus provides a versatile tool to investigate mechanisms underlying mesothelioma development. We suggest that PLCB4 may be an attractive drug target for treatment of malignant mesothelioma.

*1Third Department of Internal Medicine, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan *2Department of Pathology, School of Medicine, Kurume University, Kurume, Japan

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*3Department of Cytopathology, University of the Ryukyus, Okinawa, Japan *4Laboratory of Pathology and Clinical Research, Aichi Cancer Center, Aichi Hospital, Aichi, Japan *5Division of Virology National Cancer Center Research Institute, Tokyo, Japan *6Department of Pathology and Clinical Laboratories, Nagoya University Hospital, Aichi, Japan *7Division of Molecular Oncology, Aichi Cancer Center Research Institute, Aichi, Japan *8Immuno-Biological Laboratories Co., Ltd, Gunma, Japan

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From left to right First raw: Dr. K. Kuwahara, Dr. K. Kuzushima, Dr. R. Ohta Second raw: Ms. R. Terada, Dr. N. Gondo, Ms. K. Hiramatsu, Dr. A. Demachi-Okamura Inset: Dr. Y. Akatsuka, Dr. Y. Uemura, Dr. R. Zhang, Ms. M. Tatsumi

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Division of Immunology ________________________________________________________________________________

Kiyotaka Kuzushima, M.D. Chief Kazuhiko Kuwahara, M.D. Section Head (as of April 2014) Ayako Demachi-Okamura, Ph.D. Researcher Rieko Ohta, Ph.D. Researcher (as of January 2015) Rong Zhang, Ph.D. Research Resident (until March 2015) Eri Yamada, M.D. Research Resident (until March 2014) Naomi Gondo, M.D. Research Resident (as of April 2014) Haruru Kotani, M.D. Research Resident (as of April 2015 until September 2015) Kaho Hiramatsu, Research Assistant Rie Terada, Semi-regular Employee Minako Tatsumi, Semi-regular Employee (until March 2015) Keiko Shiraishi, Semi-regular Employee Tomiko Tsuboi, Semi-regular Employee Hitomi Asai, Semi-regular Employee (as of January 2014) Visiting Researcher Yoshiki Akatsuka, M.D. Department of Hematology & Oncology, Fujita Health University Yasushi Uemura, D.D.S. Division of Cancer Immunology, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center (until March 2015) Visiting Trainees Hiroyuki Maki, Department of Cellular Oncology, Nagoya University Graduate School of Medicine (until March 2014) Norihiro Ueda, M.D. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine (until March 2015)

General Summary

The object of our research is to establish molecular and cellular bases for novel cancer therapy taking advantage of immune responses. In addition, studies of breast cancer have been initiated as of 2014 to focus on development of future immunotherapy for this very common disease. The achievements during past two years were as follows. Firstly, we reported an interesting HLA-Cw7-binding peptide that cross-reacts with an HLA-A24-restricted CTL clone established from naïve CD8+ T lymphocytes stimulated with the HLA-A24-expressing TOV21G, an ovarian cancer cell line. The peptide is derived from the cellular protein, RBM4, binds to HLA-Cw7 molecules and mediates allo-reactivity. To our knowledge, this is the first peptide presented by an HLA-Cw allele and recognized by HLA-A24-restricted T-cells. Secondly, we have researched human telomerase reverse transcriptase (hTERT) as an attractive target antigen for cancer immunotherapy due to its expression in the vast majority of human tumors. We previously established an HLA-A24-restricted and hTERT461-469-specific T cell clone and demonstrated the utility of the T cell epitope for cancer immunotherapy. TCRα/β genes from the clone were transduced into CD8+ T cells from healthy adults to build a model of adoptive immunotherapy using TCR gene-modified T cells. To enhance the tumoricidal effects, we tried to use invariant NKT (iNKT) cells as a cellular adjuvant. Thirdly, we applied Yamanaka factors to reprogram human iNKT cells to pluripotency and then regenerated Vα24 invariant, TCR-expressing T lymphocytes in vitro. The regenerated iNKT (re-iNKT) cells demonstrated proliferation and IFN-γ production in response to α-galactosylceramide. They induced dendritic cell maturation and downstream activation of cancer antigen-specific cytotoxic T lymphocytes, and exhibited NKG2D- and DNAM-1-mediated natural killer cell-like cytotoxicity against cancer cell lines. In addition to the unlimited supply from induced pluripotent stem cells, the cellular adjuvant properties and a newly identified cytotoxic feature of these re-iNKT cells offer potential for development of effective immunotherapies against cancer.

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Lastly, we investigated the expression of DSS1 (deleted in split-hand/split-foot malformation 1) and chemosensitivity using DSS1-overexpressed and -knockdown breast cancer cells. Interestingly, DSS1-overexpressed cells did not show any proliferative changes, but became more resistant to chemotherapy. On the other hand, DSS1-depletion increased chemosensitivity. A similar phenotype was also observed using camptothecin, etoposide, doxorubicin, paclitaxel, and cisplatin. This result indicates that DSS1 depletion confers a drug sensitive trait against anti-cancer chemotherapy independently of BRCA2. 1. Identification of a naturally processed HLA-Cw7-binding peptide that cross-reacts with HLA-A24-restricted ovarian cancer-specific CTLs Demachi-Okamura, A., Yamada, E., Kondo, S.*1, Shibata, K.*2, Kikkawa, F.*2, and Kuzushima, K.

Cytotoxic T lymphocytes (CTLs) can exert anti-tumor effects through recognition of tumor antigen-derived peptides bound to human leukocyte antigens (HLAs) on cell surfaces. This recognition activates T-cell receptors (TCR). CTLs to probe such peptides are important reagents to define tumor antigens but generating tumor-specific CTLs usually requires autologous tumor cell lines. We have successfully induced cancer-specific CTLs using artificial antigen presenting cells (aAPCs) that have endogenous tumor-associated peptides on given HLA molecules but not their own HLAs.

We report here an HLA-A24-restricted CTL clone, which was established from naïve CD8+ T lymphocytes stimulated with aAPCs derived from TOV21G, an ovarian cancer cell line. The CTL clone responded not only to ovarian cancer cells in the context of HLA-A24 but also to allogeneic HLA-Cw7 molecules through cross-reactive TCR recognition. Using the cDNA expression cloning method, the CTL clone alloreacted, this being mediated through a nine-mer peptide derived from the TOV21G cellular protein, RBM4. The epitope peptide presented by HLA-A24 cells has yet to be identified. The CTL was demonstrated to be monoclonal on account of single positivity in tetramer staining, indicating that the HLA-A*24:02-restricted tumor-specific clone recognizes the epitope peptide presented by allo-HLA-Cw*07:02 in a cross-reactive manner. Moreover, the clone showed a requirement for peptides presented by HLA-Cw7 and the specificity for peptides was vague, implying that the TCR featured polyspecific alloreactivity.

To our knowledge, these results provide the first evidence of allorecognition of an HLA-Cw allele by HLA-A-restricted T-cells. They suggest allorecognition in certain HLA combinations, and further study is now needed to understand the mechanisms of alloreactivity to improve the prediction of alloresponses in clinical settings.

*1Department of Gynecologic Oncology, Aichi Cancer Center Hospital *2Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine 2. Interaction of Vα24 iNKT cells with dendritic cells increases the therapeutic efficacy of TCR-gene modified T cells Zhang, R., Uemura, Y.*1, Liu, T.*2, Ikeda, H.*3, Okamoto, S.*4, Tatsumi, M., Mineno, J.*4, Shiku, H.*3, and Kuzushima, K. Adoptive immunotherapy using TCR gene-modified T cells is an attractive strategy for targeting cancer. Human telomerase reverse transcriptase (hTERT) is a promising target antigen for cancer immunotherapy due to its expression in vast majority of human tumors. We previously established a HLA-A24-restricted and hTERT461-469-specific T cell clone and demonstrated the utility of the T cell epitope for cancer immunotherapy (Int J Cancer 110: 403-412). In the current study, TCRα/β genes from this T cell clone were transduced with CD8+ T cells and their anti-tumor potential was analyzed. The redirected T cells efficiently expressed the transduced TCRs and killed hTERT peptide-loaded T2-A24 cells, but never exhibited cytotoxicity against lung cancer cells expressing both HLA-A24 and hTERT. To address this issue, we used invariant NKT (iNKT) cells, a unique subset of T cells that recognize α-GalCer presented by CD1d on antigen-presenting cells, as a cellular adjuvant. We found that soluble factors from the iNKT cell/α-GalCer-dendritic cell (DC) interaction enhanced the HLA-I expression on cancer cells, thereby increasing susceptibility to cell lysis. In addition, the soluble factors upregulated both perforin and granzyme B in redirected T cells, in turn enhancing the potency of cellular immunity. Furthermore, in vivo transfer of redirected T cells in combination with iNKT/α-GalCer-DC inhibited tumor growth and significantly prolonged survival in a xenograft model. Thus, the additional transfer of iNKT/α-GalCer-DC may improve the efficacy of redirected T cells. *1Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa. *2Cancer Center, Chinese PLA General Hospital., Beijing,

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China. *3Department of Immuno-Gene Therapy, Mie University Graduate School of Medicine, Mie. *4Center for Cell and Gene Therapy, Takara Bio Inc., Shiga. 3. Cellular adjuvant properties and direct cytotoxicity in rejuvenated Vα24 invariant NKT cells from human induced pluripotent stem cells Zhang, R., Kitayama, S.*1, Liu, R.*2, Ueda, N., Tatsumi, M., Kaneko, S.*1, Kuzushima, K., and Uemura, Y.*3 Vα24 invariant natural killer T (iNKT) cells are a small subset of T lymphocytes implicated in the regulation of a broad range of immune responses. They recognize specific lipid antigens presented by CD1d on antigen-presenting cells and induce both innate and adaptive immune responses. Their powerful adjuvant properties, which enhance effective immunity against cancer, means that they represent promising therapeutic tools. However, this has been hampered by the difficulty of preparing functional iNKT cells from patients in large enough numbers to be therapeutic. To overcome this obstacle, we used Yamanaka factors to reprogram human iNKT cells to pluripotency and then regenerated Vα24 invariant, TCR-expressing T lymphocytes in vitro through optimized α-chain cytokine combination. Like the parental iNKT cells, the regenerated iNKT (re-iNKT) cells showed proliferation and IFN-γ production in response to α-galactosylceramide (α-GalCer). The re-iNKT cells also induced dendritic cell maturation and downstream activation of cancer antigen-specific cytotoxic T lymphocytes in vitro, and exhibited NKG2D- and DNAM-1-mediated natural killer cell-like cytotoxicity against cancer cell lines. In addition to their availability in an unlimited supply from induced pluripotent stem cells, the cellular adjuvant properties and a newly identified cytotoxic feature of these re-iNKT cells offer the potential for development of effective immunotherapies against cancer. *1Shin Kaneko Laboratory, Department of Cell Growth and Differentiation, Center for iPS cell Research and Application (CiRA), Kyoto University, Kyoto. *2Cancer Center, Chinese PLA General Hospital., Beijing, China. *3Division of Cancer Immunotherapy, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa. 4. Depletion of DSS1, which is a member of mammalian TREX2 complex and maintains BRCA2 stability, confers breast

cancer cells highly-sensitive to anti-cancer drugs through DNA damage Gondo, N., Rezano A.*1, Ohta, R., Kuzushima, K., Toyama, T.*2, and Kuwahara, K.

Breast cancer is a leading cause of cancer death of women all over the world. Genetic BRCA1/2 insufficiency is associated with breast cancer development, but germline mutations of the two genes have been only rarely observed in sporadic breast cancers, which account for approximately 95% of the total. Some reports have indicated that overexpression of BRCA2 significantly correlate with poor survival and worse histological findings; however, the contribution of BRCA2 to tumorigenesis or malignant progression in sporadic breast cancers still remains controversial.

DSS1 (deleted in split-hand/split-foot malformation 1), a mammalian component of the transcription/mRNA export complex, has been shown to interact with and stabilize BRCA2. We initially investigated the expression level of DSS1 mRNA using 289 samples derived from patients with sporadic breast cancers, and classified into DSS1high and DSS1low groups. Although no significant differences were observed between the groups for several parameters such as nodal status and nuclear grade, the DSS1high group showed a significant shorter survival in relapse-free survival curves, while the difference in the breast cancer-specific survival curve was not significant. These results were supported by the public database of Kaplan-Meier, designated KMplotter.

In order to clarify the significance of DSS1 levels in patient prognosis, in vitro studies using DSS1-overexpressed and -knockdown breast cancer cells were performed. DSS1-overexpressed cells did not show any proliferative changes, but became more resistant to chemotherapy. On the other hand, DSS1-depletion increased chemosensitivity. A similar phenotype was also observed using camptothecin, etoposide, doxorubicin, paclitaxel, and cisplatin. DSS1 has some binding partner such as BRCA2, 26S proteasome subunits, and TREX2 component PCID2.

We speculated that increased chemosensitivity by DSS1 depletion might be affected by BRCA2 insufficiency; however, BRCA2 knockdown showed marginal effects on chemosensitivity. This result indicates that DSS1 depletion confers a drug sensitive trait for anti-cancer chemotherapy independently of BRCA2.

*1Department of Anatomy and Cellular Biology, Universitas Padjadjaran, Bandung, Indonesia. *2Department of Oncology, Immunology and Surgery,

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Nagoya City University Graduate School of Medical Sciences.

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From left to right First row: Ms. R. Watanabe, Dr. C. Oneyama, Ms. M. Miyata Second row: Mr. Y. Ninomiya, Dr. T. Kanda, Mr. A. Kuwahara Inset: Dr. S. Nakasu

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Division of Microbiology and Oncology ________________________________________________________________________________

Chitose Oneyama, Ph.D. Chief (as of April 2015) Teru Kanda, M.D. Section Head Sho Nakasu, PhD. Senior Researcher Daisuke Kawashima, Ph.D. Research Resident (until March 2014) Yohei Narita, Research Assistant (until March 2014) Mamiko Miyata, Research Assistant (as of April 2014) Risayo Watanabe, Semi-regular employee (as of November 2015) Visiting Trainee Yuichi Ninomiya, Graduate Student, Graduate School of Science, Osaka University Atsushi Kuwahara, Graduate Student, Graduate School of Science, Osaka University

General Summary

In the Division of Microbiology and Oncology, we seek to understand the mechanisms maintaining cellular homeostasis and their dysfunction in cancer. Normal cellular homeostasis requires the coordinated regulation of signaling molecules in terms of space, time and quantity. Accumulation of genetic and epigenetic alterations or oncogenic viral infection may disrupt the stringent regulation of signaling networks and lead to cellular transformation and tumor progression. Our studies involve dissecting genes, proteins, and signaling mechanisms directly responsible for oncogenic phenotypes and identifying novel therapeutic targets. Currently, the goals of our research are to elucidate the molecular mechanisms underlying aberrant activation of Src pathways in a wide variety of human cancer cells and EBV (Epstein-Barr virus)-driven oncogenesis. During the period 2014-2015, our research interest was concentrated on the following issues: 1) Spatial regulation of Src via lipid rafts controls cancer progression; 2) microRNA-mediated gene expression controls Src-related oncogenic signaling; 3) clustered microRNAs of the Epstein-Barr virus cooperatively downregulate an epithelial cell-specific metastasis suppressor; and 4) a herpesvirus specific motif of Epstein-Barr virus DNA polymerase is required for efficient lytic genome synthesis. 1. Spatial regulation of Src via lipid rafts controls cancer progression Oneyama, C., Kuwahara, A., Miyata, M., and Watanabe, R. c-Src is upregulated in various human cancers, suggesting roles in development and progression of malignancies. However, the molecular circuits of c-Src oncogenic signaling remain elusive. We have shown that a Fer tyrosine kinase oligomer mediates and amplifies Src-induced tumor progression. Previously, we found that transformation of fibroblasts is promoted by the relocation of c-Src to non-raft membranes. Under these conditions, we identified Fer and ezrin as non-raft c-Src targets. c-Src directly activated Fer by initiating its autophosphorylation, which was further amplified by Fer oligomerization. Fer interacted with active c-Src at focal adhesion membranes and activated Fer-phosphorylated ezrin to induce cell transformation. Fer also proved crucial for cell transformation induced by v-Src or epidermal growth-factor receptor activation. Furthermore, Fer

activation was required for tumorigenesis and invasiveness in some cancer cells featuring c-Src upregulation. We propose that the Src–Fer axis represents a new therapeutic target for treatment of a subset of human cancers. 2. MicroRNA-mediated gene expression controls Src-related oncogenic signaling Oneyama, C., Ninomiya, Y., Miyata, M., and Watanabe, R. The cellular Src (c-Src) tyrosine kinase is upregulated and believed to play a pivotal role in various human cancers. However, the molecular mechanisms underlying c-Src-mediated tumor progression remain elusive. Recent studies have revealed that several microRNAs (miRNAs) function as tumor suppressors by regulating the malignancy-associated expression of signalling molecules. Aberrant expression of miRNAs is frequently observed in human cancers and should be exploited to seek related molecular targets. We have focused on miRNAs found to be involved in

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Src signalling in various cancers. We found that among the c-Src-regulated microRNAs (miRNAs), miR-27b is also repressed by activation of K-Ras ⁄ H-Ras. Inhibitor studies suggested that the phosphatidylinositol 3-kinase pathway is involved in the repression of miR-27b, a characteristic of various colon cancer cell lines and tumor tissues. Re-expression of miR-27b in human colon cancer HCT116 cells caused morphological changes and suppressed tumor growth, cell adhesion, and invasion. We also identified ARFGEF1 and paxillin as novel targets of miR-27b, and established that miR-27b-mediated regulation of ARFGEF1 is crucial for controlling anchorage-independent growth. We could further show that paxillin is important for controlling cell adhesion and invasion. Re-expression of miR-27b suppressed the activation of c-Src induced by integrin-mediated cell adhesion, suggesting that repression of miR-27b may contribute to c-Src activation in cancer cells. These findings provide strong evidence that miR-27b functions as a tumor suppressor by controlling ARFGEF1 and the paxillin ⁄ c-Src circuit at focal adhesions. Thus, we continue our focus on Src-related miRNAs, their target genes, mechanisms behind their interplay and their implications for cancer therapeutics.

3. Clustered microRNAs of the Epstein- Barr virus cooperatively downregulate an epithelial cell-specific metastasis suppressor Kanda, T., and Miyata, M. The Epstein-Barr virus (EBV) encodes its own microRNAs (miRNAs); however, their biological roles remain elusive. The commonly used EBV B95-8 strain lacks a 12-kb genomic region, known as the BamHI A rightward transcripts (BART) locus, where a number of BART miRNAs are encoded. Here, bacterial artificial chromosome (BAC) technology was used to generate an EBV B95-8 strain in which the 12-kb region was fully restored at its native locus [BART(+) virus]. Epithelial cells were stably infected with either the parental B95-8 virus or the BART(+) virus, and BART miRNA expression was shown to be successfully reconstituted in the BART(+) virus-infected cells. Microarray analyses of cellular gene expression identified N-myc downstream regulated gene 1 (NDRG1) as a putative target of BART miRNAs. The NDRG1 protein was barely expressed in B cells, highly expressed in epithelial cells, including primary epithelial cells, and strongly downregulated in BART(+) virus-infected epithelial cells of various origins. Although in vitro reporter assays identified BART22 as responsible for the NDRG1 downregulation, EBV genetic analyses revealed that BART22 was not solely involved; rather, the entire BART miRNA cluster 2 was responsible for the downregulation. Immunohistochemical analyses revealed that the NDRG1 protein level was downregulated significantly in EBV-positive nasopharyngeal carcinoma specimens. Considering that NDRG1 encodes an epithelial differentiation marker and a suppressor of metastasis, these data imply a causative relationship between BART miRNA expression and epithelial carcinogenesis in vivo.

Fig. 1. When active c-Src is liberated from lipid rafts, c-Src has close access to Fer in non-raft membranes, e.g. focal adhesions, triggering Fer autoactivation via direct phosphorylation and amplification by oligomerization of Fer, which in turn induces tumor progression by phosphorylation of downstream effectors such as ezrin.

Fig. 2. In situ hybridization (ISH) analyses of EBER expression (left panels) and immunohistochemical analyses of NDRG1 expression (right panels) in nasopharyngeal carcinoma biopsy specimens. Note NDRG1 downregulation in EBER-ISH-positive specimens. Representative images of EBER-ISH-negative (top) and EBER-ISH-positive (bottom) specimens are shown.

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4. A herpesvirus specific motif of Epstein-Barr virus DNA polymerase is required for efficient lytic genome synthesis Narita, Y., Kawashima, D., Kanda, T., Tsurumi, T., and Murata, T. The Epstein-Barr virus (EBV) is associated with several malignancies, including the Burkitt’s lymphoma and the nasopharyngeal carcinoma. To avoid such disorders, understanding the molecular mechanisms of EBV replication is important. The EBV DNA polymerase (Pol) is one of the essential factors for viral lytic DNA replication. Although it is well known that its C-terminal half, possessing DNA polymerase and 3'-5' exonuclease activity, is highly conserved among Family B Pols, the NH2-terminal half has yet to be characterized in detail. In this study, we show that a stretch of hydrophobic amino acids within the pre-NH2-terminal domain of EBV Pol plays an important role. In addition, we could identify the most essential residue for replication in the motif. These findings should shed light on molecular mechanisms of viral DNA synthesis and help in development of new herpesvirus treatments.

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From left to right

First row: Dr. R. Kajino, Dr. T. Fujishita, Dr. M. Aoki, Dr. Y. Kojima, Dr. K. Sakuma Second row: Ms. H. Tamaki, Ms. Y. Itoh, Ms. N. Saito, Ms. F. Orim, Ms. Y. Goto, Ms. K. Kobori

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Division of Molecular Pathology ________________________________________________________________________________

Masahiro Aoki, M.D., D.M.Sc., Chief Keiichiro Sakuma, M.D., D.M.Sc., Senior Researcher Yasushi Kojima, M.D., D.M.Sc., Senior Researcher Rie Kajino., Ph.D. Researcher (as of April 2012) Teruaki Fujishita, D.M.Sc Researcher (as of April 2013) Yoshiko Goto, D.V.M.S., Research Assistant Noriko Saito, Research Assistant Kyoko Kobori, Research Assistant Yumiko Ito, Research Assistant Florence Orim, M.D., D.M.Sc., Research Resident (as of April 2014) Visiting Scientists Reiji Kannagi, M.D., D.M.Sc. Visiting Trainees Yukie Fuma, Kinjo Gakuin University Mark van Boxtel, Radboud University Nijmegen (until February 2014) Ryota Mitsuya, Aichi Gakuin University (as of April 2014 until March 2015) Adam Douglas, Queen’s University Belfast (as of July 2015 until August 2015)

General Summary

The incidence of colorectal cancer is increasing steadily in Japan and the disease is predicted to become the most common cancer as of 2020. Accumulating evidence suggests that in addition to genetic and epigenetic changes in the genome of cancer cells, interactions with non-cancer stromal cells play essential roles in support of colorectal cancer progression. Our research has been primarily aimed at identifying novel molecular targets for prevention and/or therapy of colorectal cancer through detailed analyses of intestinal tumor progression in genetically engineered mouse models, followed by evaluation of the findings using clinical samples. We are currently focusing on the following subjects: (1) Clarifying the roles of tumor microenvironment in cancer formation and progression; (2) Elucidating the molecular mechanisms of metastasis; and (3) Unraveling the pathophysiology of cancer cachexia. 1. An in vivo shRNA screen identifies HNRNPLL as a novel colorectal cancer metastasis suppressor Sakuma, K., Sasaki, E., Kimura, K., Komori, K., Shimizu, Y., Yatabe, Y., and Aoki, M. Despite the recent advances in treatment of colorectal cancer, the prognosis is unfavorable for patients with distant metastases. With an attempt to identify novel targets for prevention and/or therapy of colorectal cancer metastasis, we performed a functional in vivo shRNA library screen for metastasis suppressor genes using an orthotopic transplantation model. CMT93 cells, a murine colorectal cancer cell line with poor metastasizing activity, were transduced with Venus fluorescent protein and lentiviral shRNA library, and then transplanted into the rectum of C57/BL6 mice. Genomic DNA was collected from metastatic lesions, and the integrated shRNA were retrieved

by PCR for sequencing, followed by identification of the candidate genes targeted by the shRNA. Among 47 candidate genes identified, we focused on Hnrnpll (heterogeneous nuclear ribonucleoprotein L-like) gene encoding a pre-mRNA binding protein involved in pre-mRNA splicing. Hnrnpll knockdown in CMT93 cells significantly increased their matrigel invasion in vitro and lung metastasis in vivo, which could be cancelled by introducing an shRNA-resistant Hnrnpll cDNA. Interestingly, an RNA-immunoprecipitation analysis identified Cd44 as a candidate target of Hnrnpll, and the mRNA level of Cd44 variant 6 (Cd44v6), a splicing variant of Cd44 that had been shown to demarcate colon cancer stem cells driving colon cancer metastasis, was increased by knocking down Hnrnpll in colon cancer cells. Furthermore, treatment with anti-CD44v6 monoclonal antibody suppressed

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matrigel invasion of colon cancer cells induced by Hnrnpll knockdown in vitro, suggesting that Hnrnpll may suppress invasion and metastasis, at least in part, by modulating the alternative splicing of Cd44. To gain further insights into the involvement of HNRNPLL in colorectal cancer invasion and metastasis, we examined its expression during epithelial-mesenchymal transition (EMT), and found that EMT induction reduced the HNRNPLL level in SW480 cells. The link between HNRNPLL and EMT was further suggested by immunostaining analysis of clinical samples; colorectal cancer cells with low E-cadherin expression at the invasion front exhibited decreased HNRNPLL expression as compared with those in the tumor center. These results suggest that HNRNPLL is a novel metastasis suppressor in colorectal cancer. 2. Simultaneous inhibition of mTOR and EGFR suppresses invasion of intestinal adenocarcinoma in cis-Apc+/Δ716 Smad4+/- mice Fujishita, T., Kojima, Y., Kajino, R., Taketo, MM.*1, and Aoki, M. Activation of the mechanical target of rapamycin (mTOR) signaling is implicated in various human cancers. We previously reported that activation of mTOR complex 1 (mTORC1) was required for expansion of adenomatous polyps that developed in the intestines of Apc+/ △ 716 mice. However, the roles of the mTOR signaling in invasive intestinal adenocarcinomas have remained elusive. Treatment of cis-Apc+/ △ 716/Smad4+/– (cis-Apc/Smad4) mice, a mouse model of locally-invasive intestinal adenocarcinoma, with the mTORC1 inhibitor everolimus significantly suppressed expansion of their tumors. Moreover, the ATP-competitive mTOR kinase inhibitor AZD8055 suppressed the growth of intestinal adenocarcinomas more potently than everolimus. However, both everolimus and AZD8055 failed to reduce the depth of tumor invasion. Western-blot and immunohistochemistry analyses revealed activation of EGFR and its downstream signaling in the AZD8055-resistant tumors. Although single treatment with the EGFR inhibitor erlotinib showed little inhibitory effects on adenocarcinoma formation in cis-Apc/Smad4 mice, combination treatment with AZD8055 and erlotinib strongly suppressed both the expansion and invasion of the adenocarcinomas. These results suggest that feedback activation of EGFR is involved in the resistance of invasive intestinal adenocarcinomas against mTOR inhibition in vivo, and that mTOR

suppression sensitizes them to EGFR inhibition. Our findings may provide a rationale for combination therapy with EGFR inhibitors and mTOR kinase inhibitors for colon cancer patients. *1Department of Pharmacology, Graduate School of Medicine, Kyoto University 3. The MEK/ERK signaling inhibition suppresses intestinal polyp formation by reducing the stromal COX-2 and CCL2 levels Fujishita, T., Kajino, R., Kojima, Y., Taketo, MM.*1, and Aoki, M.

Frequent mutations in the KRAS gene in colon cancer suggest that inhibition of the MEK/ERK signaling can benefit colon cancer patients. However, the precise roles of the signaling in intestinal tumor formation remain to be elucidated. We found that the MEK/ERK signaling was frequently activated in stromal cells, such as vascular endothelial cells and fibroblasts, rather than in adenoma epithelial cells in intestinal polyps of ApcΔ716 mice. Treatment with the MEK inhibitor trametinib suppressed intestinal polyp formation, accompanied by reduced adenoma cell proliferation and angiogensis. Trametinib treatment reduced the cyclooxgenase-2 (COX-2) level both in primary cultures of intestinal fibroblasts and in ApcΔ716 polyps. Moreover, the level of chemokine (C-C motif) ligand 2 (CCL2), a chemokine implicated in formation of Apc mutant polyps, was reduced in fibroblasts treated in vitro with trametinib or the COX-2 inhibitor rofecoxib, as well as in the polyps of trametinib-treated ApcΔ716 mice. These results suggest that the stromal MEK/ERK signaling promotes intestinal polyp expansion through production of COX-2, which can up-regulate the pro-inflammatory chemokine CCL2. *1Department of Pharmacology, Graduate School of Medicine, Kyoto University

Fig.1. Schematic representation of the roles of the stromal MEK/ERK signaling in intestinal adenoma formation in Apc mutant mice.

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The front cover of Cancer Science highlighting the work by Fujishita T et al (3). Immunofluorescence staining for p-ERK (green) and vimentin (mesenchymal cell marker, red) in small intestinal polyps of ApcΔ 716 mice using

confocal lase scanning microscopy. Nuclei are stained with DAPI (blue).

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From left to right

First row: Ms. Y. Takada, Dr. S. Era, Ms. K. Kobori, Dr. H. Goto, Ms. N. Tanigawa Second row: Dr. H. Tanaka, Dr. H. Inaba, Dr. M. Inagaki, Ms. E. Kawamoto, Dr. K. Kasahara,

Dr. I. Izawa, Dr. Y. Hayashi, Dr. A. Inoko Inset: Dr. M. Matsuyama, Dr. D. He, Dr. Z. Wang, Ms. C. Yuhara, Ms. Y. Itoh, Dr. P. Li

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Division of Biochemistry ________________________________________________________________________________

Masaki Inagaki, M.D., Ph.D. Chief Ichiro Izawa, M.D., Ph.D. Section Head Hidemasa Goto, M.D., Ph.D. Section Head Akihito Inoko, M.D., Ph.D. Senior Researcher Kousuke Kasahara, Ph.D. Researcher Yuko Hayashi, Ph.D. Research Assistant Hiroki Tanaka, D.D.S. Ph.D. Research Resident Hironori Inaba, Ph.D. Research Resident Hiroyuki Makihara, Research Resident (as of April 2015) Saho Era, Ph.D. Research Resident (until September 2014) Kyoko Kobori, Semi-regular Employee (until December 2014) Eriko Kawamoto, Semi-regular Employee Naomi Tanigawa, Semi-regular Employee Visiting Scientists Hiromasa Aoki, Graduate School of Pharmaceutical Sciences, Nagoya City University Hiroyuki Makihara, Graduate School of Dentistry, Aichi Gakuin University (as of April 2015)

General Summary

Tetraploidy, a state in which cells have doubled chromosomal sets, is observed in ~20% of solid tumors and is considered to frequently precede aneuploidy in carcinogenesis. Tetraploidy is also detected during tissue differentiation and with aging processes. We have generated knock-in mice featuring vimentin with mitotic phosphorylation-defective mutations to impair cytokinesis. Homozygotic (VIMSA/SA) mice presented with cataracts and impaired wound healing. We found that some subcutaneous tetraploid fibroblasts caused by cytokinetic failure enter a new cell cycle and then develop into aneuploid fibroblasts in vivo, which promotes premature aging. We therefore suggest that tetraploidy without genetic alteration of cancer-related genes may be associated with premature aging rather than carcinogenesis.

Non-motile primary cilia are microtubule-based sensory organelles that regulate a number of signaling pathways during development and tissue homeostasis. Tumor cells are known to often lack primary cilia, but whether their loss is directly linked to tumorigenesis is completely unclear. We have recently found that ubiquitin-proteasome machinery removes trichoplein, a negative regulator of ciliogenesis, from mother centrioles and thereby causes Aurora-A inactivation, leading to ciliogenesis. We have identified KCTD17 as a substrate-adaptor for Cul3-RING E3 ligases (CRL3s) that polyubiquitylates trichoplein. Depletion of KCTD17 specifically arrests ciliogenesis at the initial step of axoneme (ciliary microtubule doublet) extension through aberrant trichoplein-Aurora-A activity. These results strongly indicate that the ubiquitin proteasome pathway is critically involved in the regulation of primary cilia formation. 1. Ndel1 is a suppressor of primary cilia assembly Inaba, H., Goto, H., Kasahara, K., Inoko, A., He, D., Tanigawa, N., Hayashi, Y., Kobori, K., Kumamoto, K.*1, Yonemura, S.*2, Goshima, N.*3, Yamano S.*4, Wanibuchi, H.*4, Kiyono, T.*5, Hirotsune, S.*1, and Inagaki, M. The primary cilium projects from cell surfaces and is considered to function as a chemo- and/or a mechano-sensor. Dysfunction of a primary cilium is associated with a broad spectrum of diseases such as polydactyly, obesity and polycystic kidney disease. In addition, loss of cilia is associated with various types of cancer. We previously showed that primary cilia

reassembly is suppressed by trichoplein-mediated Aurora-A activation in growing cells. We found that Ndel1, a well-known modulator of dynein activity, localizes at the subdistal appendage of the mother centriole, which nucleates a primary cilium. In the presence of serum, Ndel1 depletion reduced trichoplein at the mother centriole and induced unscheduled primary cilia formation, which was reversed by forced trichoplein expression or co-knockdown of KCTD17 (an E3 ligase component protein for trichoplein). Serum starvation induced transient Ndel1 degradation, subsequent to the disappearance of trichoplein at the mother centriole. Forced expression of Ndel1

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suppressed trichoplein degradation and axonemal microtubule extension during ciliogenesis, similar to trichoplein induction or KCTD17 knockdown. Most importantly, the proportion of ciliated and quiescent cells was increased in kidney tubular epithelia of newborn Ndel1-hypomorphic mice. In addition, we found obesity in Ndel1-hypomorphic mice, which is frequently observed in cilia-related diseases. Thus, Ndel1 acts as a novel upstream regulator of the trichoplein-Aurora-A pathway to inhibit primary cilia assembly. These findings pave the way for future studies evaluating the importance of cilia dynamics in carcinogenesis. Departments of *1Genetic Disease Research and *4Molecular Pathology, Osaka City University Graduate School of Medicine *2RIKEN Center for Life Science Technologies (Ultrastructural Research Team) *3Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced Industrial Science and Technology (AIST) *5Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute 2. The ubiquitin-proteasome system controls primary cilia formation at the initial step of axoneme extension Kasahara, K., Aoki H., Kawamoto E., Kawakami Y.*1, Kiyono T.*2, Kawamura Y.*3, Goshima N.*1, and Inagaki M. Non-motile primary cilia are microtubule-based sensory organelles that regulate a number of signaling pathways during development and tissue homeostasis. Defects in primary cilia formation (ciliogenesis) result in numerous diseases and disorders commonly known as ciliopathies. Primary cilia are grown from modified centrioles called basal bodies in response to cell cycle exit or entry into quiescence, and this process is achieved through coordinated interactions between positive and negative regulators of ciliogenesis. However, the regulatory mechanisms of ciliogenesis remain to be determined in detail. The ubiquitin-proteasome system (UPS) controls most aspects of cell physiology including cell cycling and organelle biogenesis. In this study, we identified a newly recognized role of the UPS in ciliogenesis. Using human RPE1 (telomerase reverse transcriptase-immortalized retinal pigment epithelia) cells, we could show that proteasome activity is essential for ciliogenesis and destruction of trichoplein, a centriolar protein that negatively regulates ciliogenesis through activation of Aurora-A kinases. Trichoplein is rapidly degraded in a polyubiquitylation-dependent fashion during

serum starvation-induced ciliogenesis. Using protein array and siRNA screens, we identified KCTD17 as a substrate adaptor for Cul3-RING E3 ligase (CRL3) that polyubiquitylates trichoplein. SiRNA-mediated KCTD17 depletion prevented trichoplein degradation and inactivation of Aurora-A, thereby leading to defective ciliogenesis after serum starvation. These phenotypes were rescued by expression of siRNA-resistant Myc-tagged KCTD17 or co-silencing of trichoplein, and recapitulated by expression of non-degradable trichoplein mutant. Similar to KCTD17 loss, Cul3 depletion also blocked ciliogenesis and trichoplein degradation. These results indicate that CRL3KCTD17 ubiquitin E3 ligase promotes ciliogenesis by destroying trichoplein. Maintenance of normal trichoplein levels is essential for cell cycle progression through regulating ciliogenesis, as excessive trichoplein suppresses unscheduled ciliogenesis in non-proliferating cells, whereas its depletion leads to unscheduled ciliogenesis in proliferating cells. Our study revealed that UPS controls degradation of trichoplein to promote ciliogenesis. We propose that UPS deficiency serves as a potential underlying mechanism of ciliogenesis, and that UPS regulation might provide a novel means of ciliopathy treatment. *1Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology *2Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute *3Japan Biological Informatics Consortium (JBiC) 3. Cytokinetic failure induces aneuploidy and aging in vimentin Tanaka, Hir., Goto, H., Inoko, A., Hayashi, Y., Kobori, K., Tanigawa, N., Makihara, H., Izawa, I., and Inagaki, M. Intermediate filaments (IFs), together with microtubules and actin filaments, form the cytoskeletal framework in the cytoplasm of eukaryotic cells. Distinct from the other two major cytoskeletal networks, IF component proteins are divided into six groups and their composition depends on tissue type and differentiation step. Vimentin, a type III IF protein conserved in vertebrate evolution, is expressed in all mesenchymal cells and highly in lens tissue. There is increasing evidence that IF disassembly is regulated by phosphorylation of Ser/Thr residues in the amino-terminal head domains of IF proteins. Site- and phosphorylation state-specific antibodies that can recognize a phosphorylated residue and its flanking sequence

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are powerful tools to demonstrate site (domain)-specific IF phosphorylation in cells. Using these antibodies, we first showed that mitotic IF phosphorylation is regulated by distinct protein kinases in a spatiotemporally regulated manner. Further detailed studies revealed that several mitotic kinases such as Aurora-B, Cdk1, Plk1, and Rho-kinase, participate in mitotic phosphorylation of type III IF proteins. On transient expression of type III IF proteins mutated at these mitotic phosphorylation sites to Ala in type III IF-deficient T24 cell line, we found that disturbance of mitotic IF phosphorylation induced an abnormal IF structure (referred to as an IF bridge) connecting two daughter cells during the cytokinetic process. These findings indicated that mitotic IF phosphorylation is essential for efficient separation of IFs into two daughter cells. Cells with an IF bridge appeared to make two distinct decisions regarding cell fate. The IF bridge was often torn off the two daughter cells, likely by cell-adhesion-dependent traction force, resulting in the completion of cytokinesis. With the other type cells failed in cytokinesis, resulting in formation of binucleate (multinucleate) cells. However, the significance of mitotic IF phosphorylation during organogenesis and tissue homeostasis remains largely unknown. In a previous study, we generated knock-in mice expressing vimentin that harbors mutations in mitotic phosphorylation sites. Homozygotic mice (VIMSA/SA) presented with microophthalmia and lens cataracts, whereas heterozygotic mice (VIMWT/SA) were indistinguishable from the wild type (VIMWT/WT) . In VIMSA/SA mice, lens epithelial cells were reduced in number and exhibited chromosomal instability (CIN), featuring binucleation and aneuploidy. Electron microscopic analyses revealed that lens fiber cells of VIMSA/SA mice exhibited membrane disorganization similar to defects in age-related cataracts. Since the mRNA level of the senescence (aging)-related gene was significantly elevated in the lens of VIMSA/SA, the lens phenotypes in VIMSA/SA suggested a possible causal relationship between CIN and premature aging. In our present study, we addressed whether binucleate tetraploidy precedes aneuploidy or whether these events occur independently by analyzing dorsal skin wound healing in VIMSA/SA mice. In response to skin injury, vimentin expression was elevated in wound areas of subcutaneous fibroblasts in a genotype-independent manner. During the acute phase of wound healing when vimentin expression was relatively high,

IF-bridge formation, binucleation (tetraploidy), and extra-centrosome formation were observed specifically in VIMSA/SA fibroblasts. These cellular structures disappeared with decreased vimentin expression, leading to increased numbers of aneuploid fibroblasts. Subsequently, VIMSA/SA fibroblasts exhibited a significant elevation of major senescence-related markers. These abnormalities resulted in impaired wound healing, one premature aging phenotype. 4. Novel platform for integrating centrosomal functions Inoko, A., Hayashi, Y., Kiyono, T.*1, Goshima, N.*2, and Inagaki, M. Centrosomes are small but exhibit dynamic conformational changes during cell proliferation and differentiation, featuring self-duplication, spindle pole formation and primary cilia assembly. Diseases related to centriolar abnormalities have been reported, like microcephaly, malformations and ciliopathies. Also, cancer cells are believed to lack primary cilia. Our past findings are that (1) forced ciliation results in cell cycle exit even in growing media and (2) an endogenous mechanism for primary cilia kinetics is the switching of centriolar Aurora-A mitotic kinase activity through trichoplein. These findings gave us the idea that the centrosome might be a novel therapeutic target. In fact, Aurora-A knockdown is effective for cultured cancer cell-specific mitotic defects due to the lack of the ability to form primary cilia. Our subsequent screening of novel targets that regulate centriolar dynamics is ongoing. Regarding our previous finding of a protein with similarity to trichoplein, we have now established its localization on centrosomes and relations to both centriolar duplication and spindle pole separation. With its antibodies and exogenous expression, precise centriolar localization at proximal edges and on mother centriole-specific distal appendages, responsible for integrating centrosomal function, proved possible. Its knockdown cells failed to demonstrate any of the following centrosomal functions: ciliation, centriolar duplication and spindle pole separation. Investigations are continuing to provide more precise understanding of phenomena and the underlying molecular mechanisms. *1Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute *2Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial Science and Technology

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From left to right Dr. M. Inagaki, Dr. H. Kumimoto, Mr. Y. Minoura, Mr. Y. Nishikawa, Ms. Y. Shinohara, and Dr. H. Nakamura

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Central Service Unit ________________________________________________________________________________

Masaki Inagaki, M.D. Chief Hiroshi Kumimoto, Ph.D. Senior Researcher Yasushi Minoura, B.P., Research Assistant (until March 2015) Yukiko Nakai, B.P., Research Assistant (as of April 2015) Yasushi Minoura, B.P., Senior Research Assistant (as of April 2015) Hiromu Nakamura, D.M.Sc. Senior Semi-regular Research Assistant Yasuhiro Nishikawa, Semi-regular Employee Yoshimi Shinohara, Semi-regular Employee Naomi Tanigawa, Semi-regular Employee Visiting Trainees Erika Ito, M.D. School of Medicine, Nagoya City University (until March 2014)

General Summary

Our main research project is molecular epidemiologic analysis of human esophageal cancer. In particular, we have focused on the relationship between numbers of polymorphisms in the D-loop region of mitochondrial DNA (mtDNA) and risk of esophageal cancer development. 1. Relationship between risk of esophageal cancer and the number of polymorphisms in mitochondrial DNA Kumimoto, H. Mitochondria are well known as the organelles in eucaryotes responsible for production of energy for cells and also they have well-defined roles in apoptosis. Recently, frequent mutations in mitochondrial DNA (mtDNA) have been found in various types of cancer, such as breast cancer and stomach cancer. Our previous analysis of mutations in the D-loop region of mtDNA in esophageal tumors demonstrated frequent somatic mutations (in 34 % of cases). We also determined nuclear genomic instability, but did not find any correlation with somatic mtDNA mutations, suggesting that instability of mtDNA in esophageal cancer might be independent of nuclear genomic instability. Energy as ATP is produced in mitochondria with reactive oxygen species (ROS) as by-products. Polymorphisms in the genes related to proteins of oxidative phosphorylation may thus elevate ROS production by leaking electrons. Therefore, the number of polymorphisms in mtDNA may influence ROS levels in cells, which would be

expected to increase the risk of introducing mutations into mtDNA and nuclear genomic DNA. In accordance, we analyzed the number of polymorphisms in mtDNA as a surrogate marker for ROS level, then evaluating the relationship with risk of esophageal cancer. We performed sequencing analysis of D-loop region in mtDNA using DNA samples from esophageal cancer subjects and non-cancer controls collected in the HERPACC study. At first, we used re-sequencing primers sets created by ABI, mitoSEQr. We found that the whole D-loop region could be sequenced with 4 of 8 primer sets of mitoSEQr. After sequencing the whole D-loop region, we identified polymorphisms by comparing these sequences with the common mtDNA sequence. So far, we have completed analyses of polymorphisms in 66 subjects with esophageal cancer and 67 non-cancer controls (see Table 1). After analyses of polymorphisms in 185 esophageal cancer patients and 185 non-cancer controls, we will evaluate the relationship between esophageal cancer risk and numbers of mitochondrial polymorphisms.

Table 1. Summary of analyses of

polymorphism in mtDNA Data are shown as average numbers / subject

except 'number of subjects analyzed'.

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Librarians ________________________________________________________________________________

From left to right

Mr.T.Matsunaga, Ms.T.Yasuda, Ms.M.Sasanuma, Ms.M.Namura

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Publications ______________________________________________________________________________________

Journals J001. Ali, AM, Schmidt, MK, Bolla, MK, Wang, Q, Gago-Dominguez, M, Castelao, JE, Carracedo, A, Garzon, VM, Bojesen, SE, Nordestgaard, BG, Flyger, H, Chang-Claude, J, Vrieling, A, Rudolph, A, Seibold, P, Nevanlinna, H, Muranen, TA, Aaltonen, K, Blomqvist, C, Matsuo, K, Ito, H, Iwata, H, Horio, A, John, EM, Sherman, M, Lissowska, J, Figueroa, J, Garcia-Closas, M, Anton-Culver, H, Shah, M, Hopper, JL, Trichopoulou, A, Bueno-de-Mesquita, B, Krogh, V, Weiderpass, E, Andersson, A, Clavel-Chapelon, F, Dossus, L, Fagherazzi, G, Peeters, PH, Olsen, A, Wishart, GC, Easton, DF, Borgquist, S, Overvad, K, Barricarte, A, Gonzalez, CA, Sanchez, MJ, Amiano, P, Riboli, E, Key, T, Pharoah, PD. Alcohol consumption and survival after a breast cancer diagnosis: a literature-based meta-analysis and collaborative analysis of data for 29,239 cases. Cancer Epidemiol Biomarkers Prev, 23: 934-945, 2014. (PMID: 24636975) J002. Amankwah, EK, Lin, HY, Tyrer, JP, Lawrenson, K, Dennis, J, Chornokur, G, Aben, KK, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, Campbell, IG, Carty, K, Chen, Z, Chen, YA, Chang-Claude, J, Cook, LS, Cramer, DW, Cunningham, JM, Cybulski, C, Dansonka-Mieszkowska, A, du Bois, A, Despierre, E, Dicks, E, Doherty, JA, Dork, T, Durst, M, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Fasching, PA, Fridley, BL, Gao, YT, Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harrington, P, Harter, P, Hasmad, HN, Hein, A, Heitz, F, Hildebrandt, MA, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY, Jim, H, Kellar, M, Kiemeney, LA, Krakstad, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Massuger, LF, Matsuo, K, McGuire, V, McLaughlin, JR, McNeish, I, Menon, U, Milne, RL, Modugno, F, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U,

Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, RP, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Pike, MC, Poole, EM, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, Schernhammer, E, Schwaab, I, Shu, XO, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, Spiewankiewicz, B, Sucheston-Campbell, L, Teo, SH, Terry, KL, Thompson, PJ, Thomsen, L, Tangen, IL, Tworoger, SS, van Altena, AM, Vierkant, RA, Vergote, I, Walsh, CS, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, YL, Yang, H, Zheng, W, Ziogas, A, Kelemen, LE, Berchuck, A, Georgia Chenevix-Trench on behalf of the, Amg, Schildkraut, JM, Ramus, SJ, Goode, EL, Monteiro, AN, Gayther, SA, Narod, SA, Pharoah, PD, Sellers, TA, Phelan, CM. Epithelial-Mesenchymal Transition (EMT) Gene Variants and Epithelial Ovarian Cancer (EOC) Risk. Genet Epidemiol, 2015. (PMID: 26399219) J003. Arita, K., Tsuzuki, S., Ohshima, K., Sugiyama, T., Seto, M.: Synergy of Myc, cell cycle regulators and the Akt pathway in the development of aggressive B-cell lymphoma in a mouse model. Leukemia, 28: 2270-2272, 2014. (PMID: 25034145) J004. Asai, H., Fujiwara, H., Kitazawa, S., Kobayashi, N., Ochi, T., Miyazaki, Y., Ochi, F., Akatsuka, Y., Okamoto, S., Mineno, J., Kuzushima, K., Ikeda, H., Shiku, H., Yasukawa, M.: Adoptive transfer of genetically engineered WT1-specific cytotoxic T lymphocytes does not induce renal injury. J Hematol. Oncol., 7:3, 2014. (PMID: 24393438) J005. Bargagna-Mohan, P., Lei, L., Thompson, A., Shaw, C., Kasahara, K., Inagaki, M., Mohan, R.: Vimentin phosphorylation underlies myofibroblast sensitivity to withaferin A in vitro and during corneal fibrosis. PLoS One, 17: e0133399, 2015. (PMID: 26186445) J006. Brenner, DR, Amos, CI, Brhane, Y, Timofeeva, MN, Caporaso, N, Wang, Y, Christiani, DC, Bickeboller, H, Yang, P, Albanes, D, Stevens, VL, Gapstur, S, McKay, J, Boffetta, P, Zaridze, D, Szeszenia-Dabrowska, N, Lissowska, J, Rudnai, P, Fabianova, E, Mates, D, Bencko, V, Foretova, L,

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Janout, V, Krokan, HE, Skorpen, F, Gabrielsen, ME, Vatten, L, Njolstad, I, Chen, C, Goodman, G, Lathrop, M, Vooder, T, Valk, K, Nelis, M, Metspalu, A, Broderick, P, Eisen, T, Wu, X, Zhang, D, Chen, W, Spitz, MR, Wei, Y, Su, L, Xie, D, She, J, Matsuo, K, Matsuda, F, Ito, H, Risch, A, Heinrich, J, Rosenberger, A, Muley, T, Dienemann, H, Field, JK, Raji, O, Chen, Y, Gosney, J, Liloglou, T, Davies, MP, Marcus, M, McLaughlin, J, Orlow, I, Han, Y, Li, Y, Zong, X, Johansson, M, Investigators, E, Liu, G, Tworoger, SS, Le Marchand, L, Henderson, BE, Wilkens, LR, Dai, J, Shen, H, Houlston, RS, Landi, MT, Brennan, P, Hung, RJ. Identification of lung cancer histology-specific variants applying Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia. Carcinogenesis, 36: 1314-1326, 2015. (PMID: 26363033) J007. Cai, Q, Zhang, B, Sung, H, Low, SK, Kweon, SS, Lu, W, Shi, J, Long, J, Wen, W, Choi, JY, Noh, DY, Shen, CY, Matsuo, K, Teo, SH, Kim, MK, Khoo, US, Iwasaki, M, Hartman, M, Takahashi, A, Ashikawa, K, Matsuda, K, Shin, MH, Park, MH, Zheng, Y, Xiang, YB, Ji, BT, Park, SK, Wu, PE, Hsiung, CN, Ito, H, Kasuga, Y, Kang, P, Mariapun, S, Ahn, SH, Kang, HS, Chan, KY, Man, EP, Iwata, H, Tsugane, S, Miao, H, Liao, J, Nakamura, Y, Kubo, M, Consortium, DG-O, Delahanty, RJ, Zhang, Y, Li, B, Li, C, Gao, YT, Shu, XO, Kang, D, Zheng, W. Genome-wide association analysis in East Asians identifies breast cancer susceptibility loci at 1q32.1, 5q14.3 and 15q26.1. Nat Genet, 46: 886-890, 2014. (PMID: 25038754) J008. Camargo, MC, Kim, WH, Chiaravalli, AM, Kim, KM, Corvalan, AH, Matsuo, K, Yu, J, Sung, JJ, Herrera-Goepfert, R, Meneses-Gonzalez, F, Kijima, Y, Natsugoe, S, Liao, LM, Lissowska, J, Kim, S, Hu, N, Gonzalez, CA, Yatabe, Y, Koriyama, C, Hewitt, SM, Akiba, S, Gulley, ML, Taylor, PR, Rabkin, CS. Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: an international pooled analysis. Gut, 63: 236-243, 2014. (PMID: 23580779) J009. Chew, SH., Okazaki, Y., Nagai, H., Misawa, N., Akatsuka, S., Yamashita, K., Jiang, L., Yamashita, Y., Noguchi, M., Hosoda, K., Sekido, Y., Takahashi, T., Toyokuni, S.: Cancer-promoting role of adipocytes in asbestos-induced mesothelial carcinogenesis through dysregulated adipocytokine

production. Carcinogenesis, 35: 164-72, 2014. (PMID: 23917077) J010. Chihara, D, Ito, H, Izutsu, K, Hattori, M, Nishino, Y, Ioka, A, Matsuda, T, Ito, Y. Advance and stagnation in the treatment of patients with lymphoma and myeloma: Analysis using population-based cancer registry data in Japan from 1993 to 2006. Int J Cancer, 137: 1217-1223, 2015. (PMID: 25694231) J011. Chihara, D, Ito, H, Katanoda, K, Shibata, A, Matsuda, T, Sobue, T, Matsuo, K. Incidence of myelodysplastic syndrome in Japan. J Epidemiol, 24: 469-473, 2014. (PMID: 25088696) J012. Chihara, D, Ito, H, Matsuda, T, Shibata, A, Katsumi, A, Nakamura, S, Tomotaka, S, Morton, LM, Weisenburger, DD, Matsuo, K. Differences in incidence and trends of haematological malignancies in Japan and the United States. Br J Haematol, 164: 536-545, 2014. (PMID: 24245986) J013. Chihara, D, Ito, H, Matsuo, K. Comparison of the incidence and trends of hematologic malignancies between Japan and the United States. Rinsho Ketsueki, 56: 366-374, 2015. (PMID: 25971266) J014. Chihara, D, Izutsu, K, Kondo, E, Sakai, R, Mizuta, S, Yokoyama, K, Kaneko, H, Kato, K, Hasegawa, Y, Chou, T, Sugahara, H, Henzan, H, Sakamaki, H, Suzuki, R, Suzumiya, J. High-dose chemotherapy with autologous stem cell transplantation for elderly patients with relapsed/refractory diffuse large B cell lymphoma: a nationwide retrospective study. Biol Blood Marrow Transplant, 20: 684-689, 2014. (PMID: 24492141) J015. Chihara, D, Kagami, Y, Kato, H, Yoshida, N, Kiyono, T, Okada, Y, Kinoshita, T, Seto, M. IL2/IL-4, OX40L and FDC-like cell line support the in vitro tumor cell growth of adult T-cell leukemia/lymphoma. Leuk Res, 38: 608-612, 2014. (PMID: 24679586) J016. Chornokur, G, Lin, HY, Tyrer, JP, Lawrenson, K, Dennis, J, Amankwah, EK, Qu, X, Tsai, YY, Jim, HS, Chen, Z, Chen, AY, Permuth-Wey, J, Aben, K, Anton-Culver, H, Antonenkova, N, Bruinsma, F, Bandera, EV, Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A,

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J104. Sato-Otsubo, A., Nannya, Y., Kashiwase, K., Onizuka, M., Azuma, F., Akatsuka, Y., Ogino, Y., Satake, M., Sanada, M., Chiba, S., Saji, H., Inoko, H., Kennedy, G.C., Yamamoto, K., Morishima, S., Morishima, Y., Kodera, Y., Sasazuki, T., Ogawa, S. Genome-wide surveillance of mismatched alleles for graft versus host disease in stem cell transplantation. Blood. 2015 Oct 2. pii: blood-2015-03-630707. [Epub ahead of print] (PMID: 26432889) J105. Shitara, K, Matsuo, K, Muro, K, Doi, T, Ohtsu, A. Correlation between overall survival and other endpoints in clinical trials of second-line chemotherapy for patients with advanced gastric cancer. Gastric Cancer, 17: 362-370, 2014. (PMID: 23736742) J106. Shitara, K, Yuki, S, Tahahari, D, Nakamura, M, Kondo, C, Tsuda, T, Kii, T, Tsuji, Y, Utsunomiya, S, Ichikawa, D, Hosokawa, A, Ishiguro, A, Sakai, D, Hironaka, S, Oze, I, Matsuo, K, Muro, K. Randomised phase II study comparing dose-escalated weekly paclitaxel vs standard-dose weekly paclitaxel for patients with previously treated advanced gastric cancer. Br J Cancer, 110: 271-277, 2014. (PMID: 24281004) J107. Suda, K., Mizuuchi, H., Murakami, I., Uramoto, H., Tanaka, F., Sato, K., Takemoto, T., Iwasaki, T., Sekido, Y., Yatabe, Y., Mitsudomi, T.: CRKL amplification is rare as a mechanism for acquired resistance to kinase inhibitors in lung cancers with epidermal growth factor receptor mutation. Lung Cancer, 85: 147-51, 2014. (PMID: 24939008) J108. Sugimoto, Y, Wakai, K, Nakagawa, H, Suma, S, Sasakabe, T, Sakamoto, T, Takashima, N, Suzuki, S, Ogawa, S, Ohnaka, K, Kuriyama, N, Arisawa, K, Mikami, H, Kubo, M, Hosono, S, Hamajima, N, Tanaka, H, Group, JMS. Associations between polymorphisms of interleukin-6 and related cytokine genes and serum liver damage markers: a cross-sectional study in the Japan Multi-Institutional Collaborative Cohort

(J-MICC) Study. Gene, 557: 158-162, 2015. (PMID: 25523094) J109. Suguro, M., Yoshida, N., Umino, A., Kato, H., Tagawa, H., Nakagawa, M., Fukuhara, N., Karnan, S., Takeuchi, I., Hocking, TD., Arita, K., Karube, K., Tsuzuki, S., Nakamura, S., Kinoshita, T., Seto, M.: Clonal heterogeneity of lymphoid malignancies correlates with poor prognosis. Cancer Sci, 105: 897-904, 2014. (PMID: 24815991) J110. Suma, S, Naito, M, Wakai, K, Sasakabe, T, Hattori, Y, Okada, R, Kawai, S, Hishida, A, Morita, E, Nakagawa, H, Tamura, T, Hamajima, N. Effects of IL6 C-634G polymorphism on tooth loss and their interaction with smoking habits. Oral Dis, 21: 807-813, 2015. (PMID: 26011111) J111. Tajika, M, Matsuo, K, Ito, H, Chihara, D, Bhatia, V, Kondo, S, Tanaka, T, Mizuno, N, Hara, K, Hijioka, S, Imaoka, H, Matsumoto, K, Nakamura, T, Yatabe, Y, Yamao, K, Niwa, Y. Risk of second malignancies in patients with gastric marginal zone lymphomas of mucosa associate lymphoid tissue (MALT). J Gastroenterol, 49: 843-852, 2014. (PMID: 23793380) J112. Tajiri, H, Nishi, J, Ushijima, K, Shimizu, T, Ishige, T, Shimizu, M, Tanaka, H, Brooks, S. A role for fosfomycin treatment in children for prevention of haemolytic-uraemic syndrome accompanying Shiga toxin-producing Escherichia coli infection. Int J Antimicrob Agents, 46: 586-589, 2015. (PMID: 26391378) J113. Tamura, T, Morita, E, Kawai, S, Sasakabe, T, Sugimoto, Y, Fukuda, N, Suma, S, Nakagawa, H, Okada, R, Hishida, A, Naito, M, Hamajima, N, Wakai, K. No association between Helicobacter pylori infection and diabetes mellitus among a general Japanese population: a cross-sectional study. Springerplus, 4: 602, 2015. (PMID: 26543737) J114. Tanahashi, K., Natsume, A., Ohka, F., Motomura, K., Alim, A., Tanaka, I., Senga, T., Harada, I., Fukuyama, R., Sumiyoshi, N., Sekido, Y., Wakabayashi, T.: Activation of Yes-Associated Protein in Low-Grade Meningiomas Is Regulated by Merlin, Cell Density, and Extracellular Matrix Stiffness. J Neuropathol Exp Neurol, 74: 704-9, 2015. (PMID: 26049897)

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J115. Tanaka, H. Advances in cancer epidemiology in Japan. Int J Cancer, 134: 747-754, 2014. (PMID: 24105756) J116. Tanaka, H., Goto, H., Inoko, A., Makihara, H., Enomoto, A., Horimoto, K., Matsuyama, M., Kurita, K., Izawa, I., Inagaki, M.: Cytokinetic failure-induced tetraploidy develops into aneuploidy, triggering skin aging in phospho-vimentin deficient mice. J Biol Chem, 290: 12984-12998, 2015. (PMID: 25847236) J117. Tanaka, H, Matsuda, T. Arrival of a new era in Japan with the establishment of the Cancer Registration Promotion Act. Eur J Cancer Prev, 24: 542-543, 2015. (PMID: 26398323) J118. Tanaka, K., Hida, T., Oya, Y., Oguri, T., Yoshida, T., Shimizu, J., Horio, Y., Hata, A., Kaji, R., Fujita, 2., Sekido, Y., Kodaira, T., Kokubo, M., Katakami, N., Yatabe, Y.: EGFR MutationImpact on DefinitiveConcurrent Chemoradiation Therapy for Inoperable Stage III Adenocarcinoma. J Thorac Oncol, [Epub ahead of print], 2015. (PMID: 26334754) J119. Tanaka, I., Osada, H., Fujii, M., Fukatsu, A., Hida, T., Horio, Y., Kondo, Y., Sato, A., Hasegawa, Y., Tsujimura, T., Sekido, Y.: LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascade. Oncogene, 34: 73-83, 2015. (PMID: 24336325) J120. Taniguchi, C, Tanaka, H, Nakamura, N, Saka, H, Oze, I, Ito, H, Tachibana, K, Tokoro, A, Nozaki, Y, Nakamichi, N, Sakakibara, H. Varenicline is more effective in attenuating weight gain than nicotine patch 12 months after the end of smoking cessation therapy: an observational study in Japan. Nicotine Tob Res, 16: 1026-1029, 2014. (PMID: 24706051) J121. Ueda, N, Chihara, D, Kohno, A, Tatekawa, S, Ozeki, K, Watamoto, K, Morishita, Y. Predictive value of circulating angiopoietin-2 for endothelial damage-related complications in allogeneic hematopoietic stem cell transplantation. Biol Blood Marrow Transplant, 20: 1335-1340, 2014. (PMID: 24796281) J122. Uemura, H, Katsuura-Kamano, S, Yamaguchi, M, Arisawa, K, Hamajima, N, Hishida, A, Kawai, S, Oze, I, Shinchi, K,

Takashima, N, Suzuki, S, Nakahata, N, Mikami, H, Ohnaka, K, Kuriyama, N, Kubo, M, Tanaka, H, Japan Multi-institutional Collaborative Cohort Study, G. A variant of the CLOCK gene and related haplotypes are associated with the prevalence of type 2 diabetes in the Japanese population. J Diabetes, 2015. (PMID: 26374515) J123. Ueno, M, Ohkawa, S, Morimoto, M, Ishii, H, Matsuyama, M, Kuruma, S, Egawa, N, Nakao, H, Mori, M, Matsuo, K, Hosono, S, Nojima, M, Wakai, K, Nakamura, K, Tamakoshi, A, Takahashi, M, Shimada, K, Nishiyama, T, Kikuchi, S, Lin, Y. Genome-wide association study-identified SNPs (rs3790844, rs3790843) in the NR5A2 gene and risk of pancreatic cancer in Japanese. Sci Rep, 5: 17018, 2015. (PMID: 26592175) J124. Wada, K, Nagata, C, Tamakoshi, A, Matsuo, K, Oze, I, Wakai, K, Tsuji, I, Sugawara, Y, Mizoue, T, Tanaka, K, Iwasaki, M, Inoue, M, Tsugane, S, Sasazuki, S, Research Group for the, D, Evaluation of Cancer Prevention Strategies in, J. Body mass index and breast cancer risk in Japan: a pooled analysis of eight population-based cohort studies. Ann Oncol, 25: 519-524, 2014. (PMID: 24412821) J125. Wang, Z, Zhu, B, Zhang, M, Parikh, H, Jia, J, Chung, CC, Sampson, JN, Hoskins, JW, Hutchinson, A, Burdette, L, Ibrahim, A, Hautman, C, Raj, PS, Abnet, CC, Adjei, AA, Ahlbom, A, Albanes, D, Allen, NE, Ambrosone, CB, Aldrich, M, Amiano, P, Amos, C, Andersson, U, Andriole, G, Jr., Andrulis, IL, Arici, C, Arslan, AA, Austin, MA, Baris, D, Barkauskas, DA, Bassig, BA, Beane Freeman, LE, Berg, CD, Berndt, SI, Bertazzi, PA, Biritwum, RB, Black, A, Blot, W, Boeing, H, Boffetta, P, Bolton, K, Boutron-Ruault, MC, Bracci, PM, Brennan, P, Brinton, LA, Brotzman, M, Bueno-de-Mesquita, HB, Buring, JE, Butler, MA, Cai, Q, Cancel-Tassin, G, Canzian, F, Cao, G, Caporaso, NE, Carrato, A, Carreon, T, Carta, A, Chang, GC, Chang, IS, Chang-Claude, J, Che, X, Chen, CJ, Chen, CY, Chen, CH, Chen, C, Chen, KY, Chen, YM, Chokkalingam, AP, Chu, LW, Clavel-Chapelon, F, Colditz, GA, Colt, JS, Conti, D, Cook, MB, Cortessis, VK, Crawford, ED, Cussenot, O, Davis, FG, De Vivo, I, Deng, X, Ding, T, Dinney, CP, Di Stefano, AL, Diver, WR, Duell, EJ, Elena, JW, Fan, JH, Feigelson, HS, Feychting, M, Figueroa, JD, Flanagan, AM, Fraumeni, JF, Jr., Freedman, ND, Fridley, BL, Fuchs, CS, Gago-Dominguez, M,

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Gallinger, S, Gao, YT, Gapstur, SM, Garcia-Closas, M, Garcia-Closas, R, Gastier-Foster, JM, Gaziano, JM, Gerhard, DS, Giffen, CA, Giles, GG, Gillanders, EM, Giovannucci, EL, Goggins, M, Gokgoz, N, Goldstein, AM, Gonzalez, C, Gorlick, R, Greene, MH, Gross, M, Grossman, HB, Grubb, R, 3rd, Gu, J, Guan, P, Haiman, CA, Hallmans, G, Hankinson, SE, Harris, CC, Hartge, P, Hattinger, C, Hayes, RB, He, Q, Helman, L, Henderson, BE, Henriksson, R, Hoffman-Bolton, J, Hohensee, C, Holly, EA, Hong, YC, Hoover, RN, Hosgood, HD, 3rd, Hsiao, CF, Hsing, AW, Hsiung, CA, Hu, N, Hu, W, Hu, Z, Huang, MS, Hunter, DJ, Inskip, PD, Ito, H, Jacobs, EJ, Jacobs, KB, Jenab, M, Ji, BT, Johansen, C, Johansson, M, Johnson, A, Kaaks, R, Kamat, AM, Kamineni, A, Karagas, M, Khanna, C, Khaw, KT, Kim, C, Kim, IS, Kim, JH, Kim, YH, Kim, YC, Kim, YT, Kang, CH, Jung, YJ, Kitahara, CM, Klein, AP, Klein, R, Kogevinas, M, Koh, WP, Kohno, T, Kolonel, LN, Kooperberg, C, Kratz, CP, Krogh, V, Kunitoh, H, Kurtz, RC, Kurucu, N, Lan, Q, Lathrop, M, Lau, CC, Lecanda, F, Lee, KM, Lee, MP, Le Marchand, L, Lerner, SP, Li, D, Liao, LM, Lim, WY, Lin, D, Lin, J, Lindstrom, S, Linet, MS, Lissowska, J, Liu, J, Ljungberg, B, Lloreta, J, Lu, D, Ma, J, Malats, N, Mannisto, S, Marina, N, Mastrangelo, G, Matsuo, K, McGlynn, KA, McKean-Cowdin, R, McNeill, LH, McWilliams, RR, Melin, BS, Meltzer, PS, Mensah, JE, Miao, X, Michaud, DS, Mondul, AM, Moore, LE, Muir, K, Niwa, S, Olson, SH, Orr, N, Panico, S, Park, JY, Patel, AV, Patino-Garcia, A, Pavanello, S, Peeters, PH, Peplonska, B, Peters, U, Petersen, GM, Picci, P, Pike, MC, Porru, S, Prescott, J, Pu, X, Purdue, MP, Qiao, YL, Rajaraman, P, Riboli, E, Risch, HA, Rodabough, RJ, Rothman, N, Ruder, AM, Ryu, JS, Sanson, M, Schned, A, Schumacher, FR, Schwartz, AG, Schwartz, KL, Schwenn, M, Scotlandi, K, Seow, A, Serra, C, Serra, M, Sesso, HD, Severi, G, Shen, H, Shen, M, Shete, S, Shiraishi, K, Shu, XO, Siddiq, A, Sierrasesumaga, L, Sierri, S, Loon Sihoe, AD, Silverman, DT, Simon, M, Southey, MC, Spector, L, Spitz, M, Stampfer, M, Stattin, P, Stern, MC, Stevens, VL, Stolzenberg-Solomon, RZ, Stram, DO, Strom, SS, Su, WC, Sund, M, Sung, SW, Swerdlow, A, Tan, W, Tanaka, H, Tang, W, Tang, ZZ, Tardon, A, Tay, E, Taylor, PR, Tettey, Y, Thomas, DM, Tirabosco, R, Tjonneland, A, Tobias, GS, Toro, JR, Travis, RC, Trichopoulos, D, Troisi, R, Truelove, A, Tsai, YH, Tucker, MA, Tumino, R, Van Den Berg, D, Van Den Eeden, SK, Vermeulen, R, Vineis, P, Visvanathan, K, Vogel, U, Wang, C, Wang, C, Wang, J, Wang, SS,

Weiderpass, E, Weinstein, SJ, Wentzensen, N, Wheeler, W, White, E, Wiencke, JK, Wolk, A, Wolpin, BM, Wong, MP, Wrensch, M, Wu, C, Wu, T, Wu, X, Wu, YL, Wunder, JS, Xiang, YB, Xu, J, Yang, HP, Yang, PC, Yatabe, Y, Ye, Y, Yeboah, ED, Yin, Z, Ying, C, Yu, CJ, Yu, K, Yuan, JM, Zanetti, KA, Zeleniuch-Jacquotte, A, Zheng, W, Zhou, B, Mirabello, L, Savage, SA, Kraft, P, Chanock, SJ, Yeager, M, Landi, MT, Shi, J, Chatterjee, N, Amundadottir, LT. Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33. Hum Mol Genet, 23: 6616-6633, 2014. (PMID: 25027329) J126. Watanabe, M, Ito, H, Hosono, S, Oze, I, Ashida, C, Tajima, K, Katoh, H, Matsuo, K, Tanaka, H. Declining trends in prevalence of Helicobacter pylori infection by birth-year in a Japanese population. Cancer Sci, 2015. (PMID: 26395018) J127. Yamada, E., Demachi-Okamura, A., Kondo, S., Akatsuka, Y., Suzuki, S., Shibata, K., Kikkawa, F., Kuzushima, K.: Identification of a naturally processed HLA-Cw7-binding peptide that cross-reacts with HLA-A24-restricted ovarian cancer-specific CTLs. Tissue Antigens, 86:164-171, 2015. (PMID: 26216489) J128. Yamaguchi, M, Uemura, H, Arisawa, K, Katsuura-Kamano, S, Hamajima, N, Hishida, A, Suma, S, Oze, I, Nakamura, K, Takashima, N, Suzuki, S, Ibusuki, R, Mikami, H, Ohnaka, K, Kuriyama, N, Kubo, M, Tanaka, H, Japan Multi-institutional Collaborative Cohort Study, G. Association between brain-muscle-ARNT-like protein-2 (BMAL2) gene polymorphism and type 2 diabetes mellitus in obese Japanese individuals: A cross-sectional analysis of the Japan Multi-institutional Collaborative Cohort Study. Diabetes Res Clin Pract, 2015. (PMID: 26497775) J129. Yamashita, R., Sato, M., Kakumu, T., Hase, T., Yogo, N., Maruyama, E., Sekido, Y., Kondo, M., Hasegawa, Y.: Growth inhibitory effects of miR-221 and miR-222 in non-small cell lung cancer cells. Cancer Med, 4: 551-64, 2015. (PMID: 25641933) J130. Yamashita, Y., Ito, Y., Isomura, H., Takemura, N., Okamoto, A., Motomura, K., Tsujiuchi, T., Natsume, A, Wakabayashi T, Toyokuni S, Tsurumi T.: Lack of presence of the

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human cytomegalovirus in human glioblastoma. Mod Pathol, 27: 922-929, 2014. (PMID: 24336154) J131. Ye, B., Dai, Z., Liu, B., Wang, R., Yang, X., Huang, G., Wang, S., Xia, P., Kuwahara, K., Sakaguchi, N., Fan, Z.: Pcid2 inactivates developmental genes in human and mouse embryonic stem cells to sustain their pluripotency by modulation of Eid1 stability. Stem Cells, 32: 623-635, 2014. (PMID: 24167073) J132. Yoshida, N., Karube, K., Utsunomiya, A., Tsukasaki, K., Imaizumi, Y., Taira, N., Uike, N., Umino, A., Arita, K., Suguro, M., Tsuzuki, S., Kinoshita, T., Ohshima, K., Seto, M.: Molecular characterization of chronic-type adult T-cell leukemia/lymphoma. Cancer Res, 74: 6129-6138, 2014. (PMID: 25320005)

J133. Yoshida, N., Tsuzuki, S., Karube, K., Takahara, T., Suguro, M., Miyoshi, H., Nishikori, M., Shimoyama, M., Tsukasaki, K., Ohshima, K., Seto, M.: STX11 functions as a novel tumor suppressor gene in peripheral T-cell lymphomas. Cancer Sci, 106: 1455-1462, 2015. (PMID: 26176172)

J134. Yusa A, Toneri T, Masuda T, Ito S, Yamamoto S, Okochi M, Kondo N, Iwata H, Yatabe Y, Ichinosawa Y, Kinuta S, Kondo E, Honda H, Arai F, Nakanishi H.: Development of a New Rapid Isolation Device for Circulating Tumor Cells (CTCs) Using 3D Palladium Filter and Its Application for Genetic Analysis.

PLoS ONE Feb 11;9(2):e88821., 2014 doi: 10.1371/journal.pone.0088821. J135. Zhang, R., Liu, T.Y., Senju, S., Haruta, M., Hirosawa, N., Suzuki, M., Tatsumi, M., Ueda, N., Maki, H., Nakatsuka, R., Matsuoka, Y., Sasaki, Y., Tsuzuki, S., Nakanishi, H., Araki, R., Abe, M., Akatsuka, Y., Sakamoto, Y., Sonoda, Y., Nishimura, Y., Kuzushima, K., Uemura, Y.: Generation of mouse pluripotent stem cell-derived proliferating myeloid cells as an unlimited source of functional antigen-presenting cells. Cancer Immunol Res., 3:668-677, 2015. (PMID: 25672396) J136. Zhang, Y, Su, HJ, Pan, KF, Zhang, L, Ma, JL, Shen, L, Li, JY, Liu, WD, Oze, I, Matsuo, K, Yuasa, Y, You, W. Methylation status of blood leukocyte DNA and risk of gastric cancer in a

high-risk Chinese population. Cancer Epidemiol Biomarkers Prev, 2014. (PMID: 25086101) J137. Zheng, W, McLerran, DF, Rolland, BA, Fu, Z, Boffetta, P, He, J, Gupta, PC, Ramadas, K, Tsugane, S, Irie, F, Tamakoshi, A, Gao, YT, Koh, WP, Shu, XO, Ozasa, K, Nishino, Y, Tsuji, I, Tanaka, H, Chen, CJ, Yuan, JM, Ahn, YO, Yoo, KY, Ahsan, H, Pan, WH, Qiao, YL, Gu, D, Pednekar, MS, Sauvaget, C, Sawada, N, Sairenchi, T, Yang, G, Wang, R, Xiang, YB, Ohishi, W, Kakizaki, M, Watanabe, T, Oze, I, You, SL, Sugawara, Y, Butler, LM, Kim, DH, Park, SK, Parvez, F, Chuang, SY, Fan, JH, Shen, CY, Chen, Y, Grant, EJ, Lee, JE, Sinha, R, Matsuo, K, Thornquist, M, Inoue, M, Feng, Z, Kang, D, Potter, JD. Burden of total and cause-specific mortality related to tobacco smoking among adults aged ≥ 45 years in Asia: a pooled analysis of 21 cohorts. PLoS Med, 11: e1001631, 2014. (PMID: 24756146)

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Reviews and Books

R001. Goto, H., Kasahara, K., Inagaki, M.: Novel insights into Chk1 regulation by phosphorylation. Cell Struct Funct, 40: 43-50, 2015. (PMID: 25748360) R002. Goto, H., Inagaki, M.: Method for generation of antibodies specific for site-and post-translational modifications. Monoclonal Antibodies, Methods and Protocols, Second Edition, “Methods in molecular biology” series, eds. Ossipow V. and Fischer N. Humana Press. 1131: 21-31, 2014. (PMID: 24515457) R003. Goto, H., Inagaki, M.: New insights into roles of intermediate filament phosphorylation and progeria pathogenesis. IUBMB Life, 66: 195-200, 2014. (PMID: 24659572) R004. Goto, H., Tanaka, H., Kasahara, K., Inagaki, M.: Phospho-specific antibody probes of intermediate filament (IF) proteins. Intermediate Filament Proteins, Methods in Enzymology, eds. Omary, B., Liem, R., Elsevier. In press. R005. Ito, H, Matsuo, K. Molecular epidemiology, and possible real-world applications in breast cancer. Breast Cancer, 2015. (PMID: 25862066)

R006. Murata, T., Tsurumi, T.: Switching of EBV cycles between latent and lytic states. Rev Med Virol, 24: 142-153, 2014. (PMID: 24339346) R007. Oneyama, C., Okada, M.: MicroRNAs as the fine-tuners of Src oncogenic signaling. J Biochem: 157(6), 431-438, 2015. (PMID: 25862810)

R008. Oneyama, C., Okada, Masato.: Spational regulation of Src via lipid rafts and cancer progression. Jikken Igaku, 33(10): 82-87, 2015. R009. Reiji Kannagi, Keiichiro Sakuma, Bi-He Cai, Shin-Yi Yu.: Tumor-associated glycans and their functional roles in the multistep process of human cancer progression. Sugar chain, 139-58, 2015. (Springer) R010. Thirion, M., Kanda, T., Murakami, Y., Ochiya, T., Iizasa, H.: MicroRNAs and oncogenic human viruses. MicroRNAs: Key Regulators of

Oncogenesis, Springer International Publishing, 155-182, 2014.

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Abstracts for international conferences

A001. Arita, K., Tsuzuki, S., Ohshima, K., Sugiyama, T., Seto, M.: Synergy of Myc, cell cycle regulators and the Akt pathway in a mouse model of B-cell lymphoma. American Society of Hematology Meeting on Lymphoma Biology, Colorado Springs, 2014. A002. Hosono, S. Polymorphisms in DNA repair genes are associated with endometrial cancer risk among Japanese women. The 19th Japan-Korea Cancer Research Workshop, Jeju Island, 2014.

A003. Inaba, H., Goto, H., Kasahara, K., Kumamoto, K., Yonemura, S., Inoko, A., Yamano, S., Wanibuchi, H., He, D., Goshima, N., Kiyono, T., Hirotsune, S., Inagaki, M.: Ndel1 suppresses unscheduled cilia formation in proliferating cells by regulating trichoplein-Aurora-A pathway. The 55th Annual Meeting of the American Society for Cell Biology, San Diego, 2015.

A004. Inagaki M.: New insights into roles of intermediate filament (IF) phosphorylation and progeria pathogenesis. The 13th biennial Gordon Conference on Intermediate Filaments, West Dover, 2014.

A005. Inagaki, M.: Cancer research on the two noteworthy issues: tetraploidy and primary cilia. Aichi Cancer Center 50th anniversary International Symposium, Nagoya, 2015.

A006. Ito, H. The risk prediction for esophaneal cancer by drinking, smoking, and the polymorphisms of ALDH2 and ADH1B. AACR ANNUAL MEETING 2015, Philadelphia, 2015.

A007. Ito, H., Oze, I., Hosono, S., Watanabe M., Tanaka, H., Matsuo, K. Cumulative risks of gastric cancer by PSCA polymorphism, Helicobacter Pylori infection and smoking history in Japan. American Association for Cancer Research ANNUAL MEETING 2014, SAN DIEGO, 2014.

A008. Ito, H., Tanaka, H. Descriptive epidemiology of cancer in the Japanese "oldest-old" population. International Association of Cancer

Registries in Ottawa, Ottawa, 2014.

A009. Kanda, T.: Roles of BART microRNAs in EBV-infected epithelial cells. EBV 50th anniversary, Oxford, 2014. A010. Kanda, T.: Regulation of cellular gene expression by EBV-encoded miRNAs in epithelial cells. 39th Annual International Herpesvirus Workshop, Kobe, 2014.

A011. Kasugai, Y., Tsuzuki, S., Yoshida, N., Suguro, M., Takahara, T., Karube, K., Ohshima, K., Seto, M.: HBZ, BCL-xL, Akt, and loss of Ink4a/Arf synergistically transform primary murine T cells and elicit adult T-cell leukemia/lymphoma (ATL)-like disease in mice. 13th International Conference of Malignant Lymphoma, Lugano, 2015.

A012. Kuwahara, K.: The role of mammalian TREX2 complex in sporadic breast cancers. The 3rd Bandung International Biomolecular Medicine Conference (BIBMC), Bandung, Indonesia, 2014.

A013. Miyama, T., Kawase, T., Kitaura, K., Chishaki R., Shibata M., Oshima, K., Hamana H., Kishi, H., Kuzushima, K., Saji, H., Suzuki, R., Ichinohe, T.: Comprehensive T-Cell Receptor Repertoire Analysis Using Deep Sequencing and Single Cell Cloning Reveals Extreme Oligoclonality of Ex Vivo Expanded Cytomegalovirus-Reactive Cytotoxic T-Cells. 57th

Annual Meeting and Exposition, American Society of Hematology, Orlando, 2015. A014. Mohan, R., Lei, L., Thompson, A., Shaw, C., Kasahara, K., Inagaki, M., Bargagna-Mohan, P.: Vimentin Phosphorylation Patterns Differentiate Corneal Fibroblasts from Myofibroblasts In Vitro and During Fibrosis. Association in Research in Vision and Ophthalmology (ARVO) meeting 2015, Colorado, 2015.

A015. Murakami-Tonami, Y., Kishida, S., Takeuchi, I., Katou, Y., Maris, J M., Ichikawa, H., Kondo, Y., Sekido, Y., Shirahige, K., Murakami, H., Kadomatsu, K.: Inactivation of SMC2 shows a Synergistic Lethal Response in MYCN-amplified Neuroblastoma Cells. Advances

66

In Neuroblastoma Research, Cologne, 2014.

A016. Nakagawa, H., Tamura, T., Mitsuda, Y., Goto, Y., Kamiya, Y., Kondo, T., Tanaka, H., Wakai, K., Hamajima, N. The association between serum ferritin levels and atrophic gastritis among Japanese adults. International Association of Cancer Registries in Ottawa, Ottawa, 2014,.

A017. Narita, Y., Murata, T., Kanda, T., Kimura, H., Tsurumi, T.: A conserved motif in the Pre-N-terminal domain of Epstein-Barr virus DNA polymerase catalytic subunit is required for the de novo EBV genome synthesis. 39th Annual International Herpesvirus Workshop, Kobe, 2014.

A018. Narita, Y., Murata, T., Kimura, H., Tsurumi, T.: A conserved motif in the Pre-N-terminal domain of Epstein-Barr virus DNA polymerase catalytic subunit is required for the de novo EBV genome synthesis. EBV 50th anniversary, Oxford, 2014.

A019. Oneyama, C.: MicroRNAs as the fine-tuners of Src oncogenic signaling. JARI&JSEV 7th Annual Meeting, Hiroshima, 2015.

A020. Sakura, T., Hayakawa, F., Sugiura, I., Imai, K., Usui, N., Fujisawa, S., Murayama, T., Yujiri, T., Kiyoi, H., Ohnishi, K., Miyazaki, Y., Ohtake, S., Kobayashi, Y., Matsuo, K.: Effectiveness of High-Dose MTX Therapy for Adult Ph-Negative ALL By Randomized Trial: JALSG ALL202-O. 57th American Society of Hematology Annual Meeting, Orlando, 2015. A021. Sekido, Y.: Hippo pathway inactivation in malignant mesothelioma cells. International Mesothelioma Interest Group, Cape Town, 2014. A022. Sekido, Y.: Hippo pathway inactivation in malignant mesothelioma cells. Keystone Symposium The Hippo Pathway: Signaling, Development and Disease, New Mexico, 2015.

A023. Sekido, Y.: Hippo pathway dysregulation in mesothelioma cells. 16th World Conference on Lung Cancer, Denver, 2015.

A024. Suguro, M., Takahara, T., Arita, K., Yoshida, N., Kakiuchi, T., Kasugai, Y., Toby, Dylan, Hocking., Takeuchi, I., Tsuzuki, S., Seto, M.: Common Progenitor Cells Give Rise to Diffuse Large B-Cell Lymphoma at Diagnosis and Relapse. American Society of Hematology Meeting on Lymphoma Biology, Colorado Springs, 2014.

A025. Tanaka, H. Advance in the Japanese Multi-Institutional Collaborative Study. 7th General Assembly and International Conference of Asian Pacific Organization for Cancer Prevention (2014 APOCP), Taipei, 2014.

A026. Tanaka H., Goto H., Inoko A., Makihara H., Izawa I., and Inagaki M.: Phosphorylation-deficient vimentin mutant mice develop premature aging via aneuploidy and cellular senescence. The 13th biennial Gordon Conference on Intermediate Filaments, West Dover, 2014.

A027. Tawara, I., Masuya, M., Kageyama, S., Nishida, T., Terakura, S., Murata, M., Fujiwara, H., Akatsuka, Y., Ikeda, H., Miyahara, Y., Tomura, D., Nukaya, I., Takesako, K., Emi, N., Yasukawa, M., Katayama, N., Shiku, H.: Adoptive Transfer of WT1-Specific TCR Gene-Transduced Lymphocytes in Patients with Myelodysplastic Syndrome and Acute Myeloid Leukemia. Blood. 126:97, 2015. 57th American Society of Hematology Annual Meeting, Orland, FL, Dec. 5, 2015.

A028. Urayama, Y. K., Takagi, M., Kawaguchi, T., Matsuo, K., Tanaka, Y., Arakawa, Y., Hasegawa, D., Yuza, Y., Kaneko, T., Noguchi, Y., Taneyama, Y., Ota, S., Inukai, T., Yanagimachi, M., Keino, D., Koike, K., Toyama, D., Nakazawa, Y., Kurosawa, H., Nakamura, K., Moriwaki, K., Goto, H., Sekinaka, Y., Morita, D., Kato, M., Koh, K., Ishida, Y., Ohara, A., Mizutani, S., Matsuda, F., Manabe, A.: Genetic Susceptibility Loci for Childhood Acute Lymphoblastic Leukemia Among Japanese. 57th American Society of Hematology Annual Meeting and Exposition, Orlando, 2015.

A029. Yoshida, N., Karube, K., Utsunomiya, A., Tsukasaki, K., Imaizumi, Y., Taira, N., Uike, N., Nakamura, S., Umino, A., Suguro, M., Tsuzuki, S., Ohshima, K., Seto. M.,: Molecular Characterization

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of Chronic-Type Adult T-Cell Leukemia/Lymphoma: Discovery of Molecular Biomarkers for Acute Transformation. American Society of Hematology Meeting on Lymphoma Biology, Colorado Springs, 2014.

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Record of Seminars ___________________________________________________________

Invited Speakers 2014 Jan. 24 Maruyama, R. (Department of Molecular Biology, Sapporo Medical University): Exploring the

possible roles of quantitatively or qualitatively abnormal long ncRNAs in gastrointestinal cancer

initiation and progression.

Mar. 25 Aoki, K. (Division of Pharmacology, University of Fukui School of Medicine): Elucidating the

mechanism of negative regulation of the colon cancer stemness.

Dec. 15 Nicole A. Najor (Department of Pathology & Department of Dermatology, Northwestern University

Feinberg School of Medicine): Role of a Desmosome-COP9 signalosome complex in epidermal

differentiation.

2015 Feb. 6 Seno, H. (Department of Gastroenterology and Hepatology, Kyoto University Graduate School of

Medicine): Cell lineage analysis reveals potency of gastrointestinal cancer stem cell markers.

Mar. 17 Nishida, Y. (Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine):

Establishing the algorithm for the treatment of desmoid tumor.

Apr. 22 Matsuo, K. (Department of Preventive Medicine, Kyushu University Faculty of Medical Sciences):

Medical research aiming at developing revolutionary cancer treatment: Multi-Omics study toward

personalized medicine.

Apr. 22 Tagawa, H. (Department of Hematology, Oncology, Nephrology, and Rheumatology, Akita

University School of Medicine): Elucidating pathophysiology of intractable hematopoietic tumors,

identification of novel therapeutic targets, and feedback to the clinic.

Apr. 22 Kotani, A. (Department of Hematology and Oncology, Tokai University School of Medicine):

Non-coding RNA as a clue to develop novel cancer medicine.

May. 19 Hirotsune, S. (Department of Genetic Disease Research, Graduate School of Medicine, Osaka City

University): Rearrangement of the microtubule network for neural cell migration.

Nov. 19 Abe, H. (Department of Chemistry, Graduate School of Science, Nagoya University): Drug

development based on nano-structured RNA technology.

Dec. 21 Watanabe, Y. (Laboratory of Chromosome Dynamics, Institute of Molecular and Cellular

Biosciences, Tokyo University): Mechanism of chromosomal instability leading to oncogenic

transformation.

Institute Speakers 2014 Jan. 10 Tanaka, K. (Molecular Oncology): Hippo pathway in mesothelioma cell lines : Elucidating

growth-inhibitory effects of AJUBA.

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Jan. 16 Fujishita, T. (Molecular Pathology): Roles of bone marrow-derived cells in colon cancer metastasis.

Feb. 21 Yoshida, N. (Molecular Medicine): Integrated genome analysis of chronic ATL and mechanism of

their blast crisis.

Feb. 27 Tanaka, H. (Biochemistry): Roles of chromosomal instability (CIN) in cancer.

May. 15 Hosono, S. (Epidemiology and Prevention): An approach for preventing endometrial cancer using

large-scale hospital-based epidemiologic data.

Jun. 19 Iioka, H. (Oncological Pathology): Functional analysis of the cell polarity regulator Crb3 in

oncogenesis.

Oct. 27 Kakiuchi, T. (Molecular Medicine): Functional involvement of dysregulated Hippo pathway in

mesothelial carcinogenesis.

Nov. 4 Kanda, T. (Virology): Future prospects of the research on infection-associated cancer.

Nov. 6 Kuwahara, K. (Immunology): Functional abnormality of GANP in sporadic breast carcinogenesis.

2015 Feb. 19 Kasahara, K. (Biochemistry): Ubiquitin-proteasome system and primary cilia.

Mar. 6 Hakiri, S. (Molecular Oncology): Characterization of inactive mutations of BAP1 in mesothelioma

cell lines.

Mar. 26 Sakuma, K. (Molecular Pathology): Identification and characterization of HNRPLL as a novel

metastasis suppressor gene of colon cancer.

Apr. 22 Tsuzuki, S. (Molecular Medicine): Current status and future prospects of my research.

Dec. 25 Kuzushima, K. (Immunology): A review of cancer immunotherapy: from Coley's toxin to immune

checkpoints. - Messages from 2015 -

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Record of Symposium ____________________________________________________________________

Aichi Cancer Center 50th Anniversary International Symposium

“Cancer Drug Resistance: Mechanisms and Strategies for Its Circumvention”

Organizing Committee: Masahiro Aoki (Chairperson), Hiroji Iwata (Vice-Chairperson), Toyoaki Hida,

Tomohiro Kinoshita, Kei Muro, Yasushi Kojima, Satoyo Hosono, Kousuke Kasahara, Yoshitaka Sekido (Advisor)

March 14, 2015, International Conference Center, Aichi Cancer Center. Program of symposium Opening Remarks: Taira Kinoshita (Aichi Cancer Center) Opening Keynote Lecture Chairperson: Masahiro Aoki (Aichi Cancer Center) Frank McCormick (University of California, San Francisco, USA) Targeting KRAS-induced stemness Session 1. Cancer Heterogeneity and Drug Resistance Chairperson: Takashi Takahashi (Nagoya University), Hiroji Iwata (Aichi Cancer Center) Matthew J. Ellis (Baylor College of Medicine, USA) Genome-directed therapeutics for endocrine therapy resistant ER+ breast cancer Tatsuhiro Shibata (National Cancer Center) Trans-ethnic landscape of hepatocellular carcinoma genomics Tetsuya Mitsudomi (Kinki University) Acquired resistance in targeted therapy against driver gene mutation in lung cancer Session 2. Cancer stem cells, tumor dormancy, and drug resistance Chairperson: Shinsuke Iida (Nagoya City University), Yoshitaka Sekido (Aichi Cancer Center) Nick Barker (A*STAR Institute of Medical Biology, Singapore)

Lgr5+ stem cells in epithelial self-renewal and cancer of the stomach and ovary Hideyuki Saya (Keio University)

Regulation of cell differentiation by actin dynamics and its application in cancer treatment Masaki Inagaki (Aichi Cancer Center)

Cancer research on the two noteworthy issues: tetraploidy and primary cilia Session 3. Strategies for circumvention of cancer drug resistance Chairperson: Yutaka Kondo (Nagoya City University), Toyoaki Hida (Aichi Cancer Center) Gianpietro Dotti (Baylor College of Medicine, USA)

T-cell therapy for cancer using gene modified T cells and strategies to overcome tumor escape or immunosuppression

Masaaki Komatsu（Niigata University） Loss of autophagy causes metabolic changes through a transcription-factor pathway

Yasuaki Arai (National Cancer Center Hospital) Interventional radiology in oncology

Closing Keynote Lecture Chairperson: Tomohiro Kinoshita (Aichi Cancer Center) Shigekazu Nagata (Kyoto University) Apoptosis and exposure of phosphatidylserine Closing Remarks: Masahiro Aoki (Aichi Cancer Center)

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Abstracts

Targeting KRAS-induced stemness Frank McCormick and Man-Tzu Wang University of California, San Francisco - Helen Diller Family Comprehensive Cancer Center, USA Of the three Ras genes, KRAS, NRAS and HRAS, KRAS is by far the major contributor to human cancer, whereas HRAS is rarely activated. In spite of this dramatic difference, KRAS and HRAS interact with the same effectors and are equally potent at transforming cells in culture. However, cells transformed by KRAS have unique properties relative to HRAS: they cause a stem-like phenotype that enables them to grow as spheres in culture, to establish tumors in mice at high efficiency and to resist the effects of multiple chemotherapy and targeted drugs. These effects are due to KRAS’ ability to bind calmodulin, and to inhibit calmodulin-dependent kinase. Low CaM kinase promotes wnt signaling and initiates a set of programs that confer stemness. Binding of K-Ras to calmodulin is prevented by phosphorylation of K-Ras on serine-181, by protein kinase C. Treatment of mice with a natural product, prostratin, that activates PKC and K-Ras phosphorylation prevents initiation of pancreatic tumors in xenograft models. Part of the “stemness” program initiated by K-Ras involves secretion of the cytokine LIF, an IL-6 family member with a unique role in maintaining stemness. Neutralization of LIF with a monoclonal antibody reduces stemness and sensitizes established pancreas tumors to gemcitabine. We propose that attacking targets in these stem-like pathways offers new opportunities for therapeutic intervention in KRAS-driven cancers. Genome-directed therapeutics for endocrine therapy resistant ER+ breast cancer Matthew J. Ellis Lester and Sue Smith Breast Center, Baylor College of Medicine, USA As a result of improvements in DNA and RNA sequencing techniques the genomic structure of estrogen receptor positive breast cancer is increasingly well documented, but extracting clinically actionable information from these complex data sets has proved fraught with difficulties. Barriers to progress include the lack of pharmacological hypotheses for novel luminal breast cancer tumor suppressor genes (e.g. MAP3K1, MLL3, SF3B1); 2) a lack of a full

understanding of interactions between mutation status, the prognosis of ER+ breast cancer, and the effectiveness of endocrine therapy; 3) an inadequate collection of patient-derived xenograft (PDX) models for luminal breast cancer that fully encompass the heterogeneity of the disease; 4) the logistical barriers of developing adjuvant strategies to exploit rare drivers present in less than 5% of tumor samples; 5) insufficient genomic discovery efforts directed towards samples accrued from patients suffering from endocrine therapy resistant disease progression and 6) an incomplete understanding of how complex somatic genotypes drive the biochemical events responsible for the “hallmarks” of luminal cancer. To better address these issues, five areas of investigation will be discussed: 1) somatic mutation diagnosis in DNA from primary breast cancer samples from patients treated with adjuvant tamoxifen and followed for over 20 years; 2) DNA and RNA sequencing of samples accrued from patients treated with neoadjuvant endocrine therapy to define the molecular origins of intrinsic aromatase inhibitor resistance and to identify pharmacological hypothesis; 3) efforts to expand and catalog patient-derived xenografts from ER+ breast cancers, including the use of mass spectrometry-based analysis of their proteomes and phosphoproteomes to expand our knowledge of the biochemistry of individual tumors; 4) a functional and pharmacological investigation of mutations in ESR1, including resistance-activating chromosomal translocations, and 5) the development of a neoadjuvant endocrine therapy strategy that identifies patients with intrinsic endocrine therapy resistance within a month of starting treatment so that they can be triaged to mutation-matched investigational treatment. Trans-ethnic landscape of hepatocellular carcinoma genomics Tatsuhiro Shibata1,2, David A. Wheeler3, and Hiroyuki Aburatani4 1Division of Cancer Genomics, National Cancer Center; 2Laboratory of Molecular Medicine, The Institute of Medical Science; 3Human Genome Sequencing Center, Baylor College of Medicine, USA; 4Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo Multiple etiological factors (hepatitis virus infection, alcohol, obesity etc) are associated with the occurrence of hepatocellular carcinoma (HCC) and their contributions diverse among ethnicity. To

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elucidate genetic diversities in HCC genomes with regards to ethnic and epidemiological differences, we have conducted the trans-ethnic cancer genome research under the umbrella of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We performed whole exome sequencing of 514 pairs of HCC, which include different ethnic populations (424 cases from the Japanese cohort and 90 from the US cohort) with various etiological backgrounds. Furthermore, whole exome data of 105 HCC cases from TCGA was included in the mutation signature analysis. Mutation call algorithms of three collaborating genome centers (National Cancer Center, Tokyo, Research Center for Advanced Science and Technology in the University of Tokyo, and Baylor College of Medicine, Houston) were adjusted and validated by the Ion Proton sequencer. In total, more than 100,000 somatic mutations were collected, and their signatures were significantly associated with ethnicity and gender, but not with the hepatitis virus status. In addition to TP53, WNT, and SWI/SNF pathways, aberrant activation of the TERT pathway by various mechanisms (promoter/coding mutations, gene amplification and viral genome integration) was found to play a central role in hepatocarcinogenesis. Aggregation of the large cancer genome data by ICGC and TCGA has rapidly progressed. In addition to the cross-tumor analysis (Pan-Cancer study), population-based meta-cancer genome analysis would provide us unique and diverse landscapes of the cancer genomes on this planet. Acquired resistance in targeted therapy against driver gene mutation in lung cancer Tetsuya Mitsudomi1, Kenichi Suda1, Hiroshi Mizuuchi1, Yoshihisa Kobayashi1, Kazuto Nishio2, and Yasushi Yatabe3 Department of Thoracic Surgery1 and Genome Biology2, Kinki Unversity Faculty of Medicine; 3Department of Pathology and Moleclular Diagnostics, Aichi Cancer Center Hospital Discovery of activating mutation of the EGFR gene in adenocarcinoma of the lung in 2004 opened the era of personalized therapy in thoracic oncology. These tumors are highly dependent on the EGFR pathway and EGFR-tyrosine kinase inhibitors (TKI) significantly prolong progression free survival in these patients compared with chemotherapy. In 2007, EML4-ALK translocation was found and these tumors are very sensitive to ALK-TKI. However, acquired resistance inevitably develops usually after a median of 10 months. The mechanisms for this resistance can be classified into

1) target gene alterations (T790M mutation in EGFR-TKI or L1196M and other mutations in ALK, 2) activation of additional kinases (e.g., MET, HER2 for EGFR, and KIT, EGFR, SRC for ALK) bypassing the inhibition of the original kinases, and 3) other mechanisms including epithelial-mesenchymal transition, small cell lung cancer transformation, etc. To overcome T790M gatekeeper mutations, so-called third generation EGFR inhibitors that selectively inhibit EGFR-T790M while sparing the wild-type EGFR are being actively developed. Likewise, ALK-TKIs of a newer generation are active at least for some of the secondary mutations found in crizotinib-resistant tumors. Tumor resistance caused by the bypass track can be coped with by combination of the inhibitors for the original kinase and the bypassing kinases. However, even with these strategies, cancer cells are smart enough to escape from the therapy using other mechanisms. Heterogeneities in terms of resistant mechanisms within a single patient become evident when specific therapeutic pressure persists. Therefore, we also need to have armamentarium that utilizes other mechanisms to cure lung cancer. Recent advances of immunotherapy targeting PD-1/PD-L1 appear attractive in this respect. These mechanism-driven therapeutic approaches will convert this fatal disease into a more chronic disorder, and eventually into a curable disease with the least patient burdens. Lgr5+ stem cells in epithelial self-renewal and cancer of the stomach and ovary Nick Barker, Marc Leushacke, Annie Ng A-STAR* Institute of Medical Biology, Singapore The availability of robust cell-surface markers for identifying and isolating adult stem cells is essential for studying both their normal in-vivo function during tissue renewal and for evaluating their contribution to cancer. Lgr5, a Wnt target gene expressing a 7-TM receptor that functions as facultative component of the Wnt receptor complex, has been shown to selectively mark stem cells in a range of rapidly renewing tissues, including the small intestine, colon, stomach, hair follicle and developing kidney. Clonal fate mapping employing the stem cell-specific Lgr5-CreERT2 line has been used to further dissect how these adult stem cell pools maintain tissue homeostasis and contribute to tissue repair following damage. Additionally, targeted in-vivo mutation of the Lgr5+ve adult stem cell pools using the same Lgr5-CreERT2 model has been used to determine the contribution of stem cells to tumor initiation and progression in various

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epithelia. A summary of the latest findings in the stomach and ovary will be presented here. Regulation of cell differentiation by actin dynamics and its application in cancer treatment Hideyuki Saya and Hiroyuki Nobuse Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University Differentiation status is strongly associated with the behavior of cancer cells. Therefore, changes in the cellular context, which regulates the differentiation potential, may serve in novel therapeutic strategies in treating cancers. We have established a mouse osteosarcoma (OS) model through overexpression of c-MYC in bone marrow stromal cells (BMSCs) derived from Ink4a/Arf (-/-) mice. In this model, we found that the loss of adipogenic potential was an essential event for OS development. Therefore, our understanding of regulatory mechanisms of adipocyte differentiation would greatly contribute to control OS tumorigenesis. Adipocytic differentiation is accompanied by the adoption of a rounded cell shape that is characteristic of mature adipocytes. Cell shape is determined primarily by the actin cytoskeleton. We have recently found a novel regulatory mechanism of adipocyte differentiation, in which regulation of transcriptional coactivator MKL1 by actin cytoskelton dynamics drives adipocyte differentiation mediated by PPARγ, a master transcriptional regulator of adipogenesis. Accordingly, adipocyte differentiation can be induced by the disruption of actin stress fibers through down-regulation of RhoA-ROCK signaling. Based on this concept, we attempted to induce adipocyte differentiation in OS cells, which resulted in a significant suppression of tumorigenesis. Induction of trans-differentiation in cancer stem cells by regulating actin cytoskeleton dynamics is a potential approach for some tumor types. Cancer research on the two noteworthy issues: tetraploidy and primary cilia Masaki Inagaki Division of Biochemistry, Aichi Cancer Center Research Institute and Department of Cellular Oncology, Nagoya University Graduate School of Medicine Tetraploidy, a state in which cells have doubled chromosomal sets, is observed in ~20% solid tumors and considered to frequently precede aneuploidy in carcinogenesis. Tetraploidy is also detected during tissue differentiation and aging process. We generated knock-in mice featuring

vimentin with mitotic phosphorylation-defective mutations to impair cytokinesis. Homozygotic (VIMSA/SA) mice presented with microophthalmia and cataracts, in which lens epithelial cells exhibited binucleation and aneuploidy, along with premature aging. We further analyzed the ability to repair wounds in the skin of VIMSA/SA mice, and found that some subcutaneous tetraploid fibroblasts caused by cytokinetic failure enter a new cell cycle and then develop into aneuploid fibroblasts in vivo, which promotes premature aging. We suggest that tetraploidy without the genetic alteration of cancer-related genes may be associated with premature aging rather than carcinogenesis. Non-motile primary cilia are microtubule-based sensory organelles that regulate a number of signaling pathways during development and tissue homeostasis. Tumor cells are known to often lack primary cilia, but whether their loss is directly linked to tumorigenesis is completely unclear. We have recently found that ubiquitin-proteasome machinery removes trichoplein, a negative regulator of ciliogenesis, from mother centrioles and thereby causes Aurora-A inactivation, leading to ciliogenesis. We have identified KCTD17 as a substrate-adaptor for Cul3-RING E3 ligases (CRL3s) that polyubiquitylates trichoplein. Depletion of KCTD17 specifically arrests ciliogenesis at the initial step of axoneme (ciliary microtubule doublet) extension through aberrant trichoplein-Aurora-A activity. We would like to discuss the relationship between primary cilia and cancer stem cells, which may be implicated in drug resistance against cancer chemotherapy. T-cell therapy for cancer using gene modified T cells and strategies to overcome tumor escape or immunosuppression Gianpietro Dotti Center for Cell and Gene Therapy, Baylor Colledge of Medicine, USA T-lymphocyte-based treatments have enormous potential in cancer patients. Over the past decade, T cells mo dified to express chimeric antigen receptors (CARs) have had clinical success in B-lymphocyte derived malignancies. In the specific context of CAR-T cells therapies for B-cell malignancies we developed at Baylor a strategy aimed at achieving antitumor effects, but limiting the prolonged B-cell aplasia caused the infusion of CD19-CAR-specific T cells. We are currently targeting the k-light chain of human immunoglobulins expressed on the cell surface of k+lymphoma cells in an effort to target lymphomas cells but spare normal l+B-lymphocytes. An update

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of the clinical trial currently ongoing will be presented. In contrast to B-cell malignancies, the clinical efficacy of CAR-T cells remains limited in solid tumors. This unfavorable outcome could be due to the insufficient migration of the infused T cells to the tumor site and to the immunosuppressive characteristics of the tumor environment, which inhibit the effector function and proliferation of those few T cells that do reach the tumor. We recently found that tumor-specific engineered T lymphocytes expanded ex vivo for adoptive T-cell therapy are defective in their capacity to degrade one critical component of the extracellular matrix. We also found that this defect can be however repaired by the ectopic expression of the enzyme heparanase. We also found that armed oncolytic viruses expressing RANTES and IL-15 can be used to favor the migration of CAR-T cells at the tumor site and promote the survival of CAR-T cells within the hostile tumor environment. Loss of autophagy causes metabolic changes through a transcription-factor pathway Masaaki Komatsu Department of Biochemistry, School of Medicine, Niigata University Autophagy provides starved cells with amino acids, free fatty acids, and glucose for new protein synthesis energy production; autophagy also controls the quality and quantity of organelles such as mitochondria. Therefore, it is plausible that autophagy might be integrated with metabolic pathways. Indeed, suppression of autophagy causes myopathy, tumorigenesis, and metabolic disorders in mice and humans. However, the metabolic changes associated with deficiencies in autophagy are largely unknown. Furthermore, it remains unclear whether the major predisposing factor for the aforementioned diseases in the absence of normal autophagic activity is a simple deficit in supply of molecular building blocks, dysregulation of mitochondrial homeostasis, or some other cause. Here, we show that deficiencies in autophagy are associated with rearrangement of glucose and glutamine metabolism via a transcriptional regulatory mechanism. Interventional radiology in oncology Yasuaki Arai National Cancer Center Hospital IR is a minimally invasive treatment modality in which small devices are percutaneously inserted into a patient’s body with minimum incision under

image guidance. There are two routes to access to the target lesion; trans-canal and direct puncture. The typical type of trans-canal approach is transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC), in which the feeding arteries are occluded with anticancer drug to kill tumor cells with stasis of blood flow. TACE could obtain total necrosis if the HCC tumor is hyper-vascular and less than 5cm in diameter. In a decade, microspheres with drug eluting and Yttrium-90 have been developed to treat HCCs with various stages. The other approach with percutaneous direct puncture is thermal ablation, such as radiofrequency ablation (RFA), microwave ablation, cryoablation for tumors in the liver, kidney, lung, etc. TACE and RFA are established as the standard treatment for early and intermediate stage HCC. Moreover, there are novel IR treatments; high-intensity focused ultrasounds (HIFU) and irreversible electroporation (IRE). HIFU kills tumor cells with thermal ablation by high-intensity focused ultrasounds without needle puncture. IRE kills tumor cells with membrane with electroporation by high voltage pulse without the destruction of anatomical structures. IR can be complementary with other treatment modalities because the mechanism of anti-tumor effect in IR is completely different from that of medical and radiation therapy. On the other hand, IR is difficult to establish evidence by clinical trials, because the clinical results in IR greatly depend on the operator’s skills and equipment. We started to conduct many multi-institutional clinical trials in Japan more earlier than western countries, however, still it is very challenging for us to establish IR as one of the standard treatments in the oncology field. Apoptosis and exposure of phosphatidylserine Shigekazu Nagata

Department of Medical Chemistry, Graduate School of Medicine, Kyoto University Apoptotic cells are swiftly engulfed by macrophages. If this process does not occur properly, materials released from dead cells activate the immune system, leading to systemic lupus erythematosus-type autoimmune disease. Phospholipids in plasma membranes are asymmetrically distributed between inner and outer leaflets, and phosphatidylserine (PtdSer) is exclusively localized in the inner leaflet. The asymmetrical distribution of phospholipids is maintained by an ATP-dependent phospholipid

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translocase or flippase. When cells undergo apoptosis, or platelets are activated, the asymmetrical distribution of phospholipids is disrupted by scramblase, leading to PtdSer-exposure. The PtdSer exposed on dead cell surface is recognized by macrophages as an “eat me” signal, while PtdSer on activated platelets provides the scaffold for clotting factors. We recently identified two membrane proteins (TMEM16F and Xkr8) as phospholipid scramblases, and a pair of membrane proteins (ATP11C and CDC50A) as a flippase. TMEM16F, a protein with

8 transmembrane regions, requires Ca2+ to support phospholipid scrambling, and plays an essential role in the PtdSer-exposure in activated platelets. Xkr8 is a protein carrying 6 transmembrane regions, and caspases cleave off its C-terminal tail to promote the scramblase activity. ATP11C is a P4-type ATPase at plasma membrane, and CDC50A works as a chaperone to transport ATO11C from endoplasmic reticulum to plasma membranes. ATP11C translocates PtdSer from outer to inner leaflets of plasma membranes in an ATP-dependent manner. When cells undergo apoptosis, ATP11C is inactivated by caspase-mediated cleavage, indicating that in addition to the caspase-mediated activation of scramblase, inactivation of flippase is required to expose PtdSer during apoptosis. Lymphoma cells that lack the flippase constitutively expose PtdSer, are engulfed by macrophages, and can not develop tumors in nude mice. These results indicate that PtdSer is necessary and sufficient as an “eat me” signal to be recognized by macrophages, and the PtdSer-expressing tumor cells can be killed by being engulfed by macrophages.

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