2014-2015) of the Aichi Cancer Center Research Institute

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

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

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.

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

iii

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

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

Organization of the Aichi Cancer Center Research Institute ______

SCIENTIFIC REPORTS

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

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.

1. Descriptive epidemiology and Information Services, National Cancer Center

1.1. Advances and set-backs/persisting 1.2. Declining trends in prevalence of problems in the treatment of lymphoma and Helicobacter pylori infection by birth-year myeloma patients: Analysis of survival in a Japanese population using population-based cancer registry Watanabe, M., Ito, H., Hosono, S., Oze, I., Ashida, C.*1, *2 *1 *3 data in Japan from 1993 to 2006 Tajima, K. , Katoh, H. , Matsuo, K. , and Tanaka, H. Chihara, D.*1, Ito, H.*2, Izutsu, K.*3, Hattori, M.*4, The age-standardized incidence and mortality rates Nishino, Y.*5, Ioka, A.*6, Matsuda, T.*7, and Ito, Y.*6 for gastric cancer have been decreasing in Japan. There have been significant advances in the This is likely to be due to some extent to a decrease treatment of patients with lymphoma and myeloma. in prevalence of Helicobacter pylori (H. pylori) Although improvements in survival outcome have infection, a major risk factor for neoplasia in the been addressed by clinical trials, such studies may stomach. Our aim was to characterize the trends in not adequately take into account changes in survival prevalence of H. pylori infection focusing on in the general patient population over time. birth-year in a Japanese population. We conducted a Therefore, we reviewed the cancer-registry data of cross-sectional study that included 4,285 subjects patients with lymphoma and myeloma in Japan who were born from 1926 to 1989. We defined H. from 1993 to 2006 and estimated relative survival pylori infection by serum H. pylori antibody titer. (adjusted for competing causes of death in Individuals having H. pylori infection and those same-age members of the general population) with negative H. pylori antibody titer but positive according to three periods of diagnosis (1993-1997, pepsinogen test were defined as high-risk 1998-2002 and 2003-2006). We also estimated individuals for gastric cancer. We estimated the conditional 5-year relative survival (5-year survival birth-year percent change (BPC) of the prevalence rate of patients who have survived 5 years). A total by Joinpoint regression analysis. The prevalence of of 26,141 patients were reviewed and analyzed. H. pylori infection among the subjects born from Relative survival improved for Hodgkin lymphoma 1927 to 1949 decreased from 54.0% to 42.0% with (HL, N = 853, +20% improvement), diffuse large a BPC of -1.2% (95%CI: -1.6% to -0.8%). This was B-cell lymphoma (DLBCL, N = 4,919, +14% followed by a rapid decline in those born between improvement) and follicular lymphoma (FL, 1949 (42.0%) and 1961 (24.0%) with a BPC of N = 1,333, +13% improvement). In contrast, we -4.5% (95%CI: -6.0% to -3.0%), and a slower found no significant improvement in survival since decline in those born between 1961 (24.0%) and 1993 with peripheral T-cell lymphoma (PTCL, 1988 (14.0%) with a BPC of -2.1% (95%CI: -3.3% N = 667, +4% improvement), adult T-cell to -0.8%). The proportion of high-risk individuals leukemia/lymphoma (ATLL, N = 2,166, -5% for gastric cancer among the subjects born from improvement) or multiple myeloma (MM, 1927 to 1942 decreased from 62.0% to 55.0% with N = 4,914, -2% improvement). Conditional 5-year a BPC of -0.8% (95%CI: -1.4% to -0.1%). A survival of HL, DLBCL, FL, PTCL, ATLL and MM subsequent rapid declining trend was observed in was 88, 87, 79, 63, 53 and 45%, respectively. those born between 1942 (55.0%) and 1972 Relative survival of patients with HL, DLBCL and (18.0%) with a BPC of -3.6% (-3.9% to -3.2%), and FL significantly improved from 1993 to 2006 in then it became stable. Thus a dramatic decline in Japan; in contrast, no improvement was seen with the prevalence of H. pylori infection was observed other related diseases, suggesting unmet needs for in those born between 1949 and 1961. As the novel treatment strategies. population attributable fraction (PAF) for H. pylori infection with gastric cancer is considerably large, *1Department of Lymphoma and Myeloma, MD this declining trend in prevalence of H. pylori Anderson Cancer Center infection would contribute to a projected future *2Department of Epidemiology, Nagoya University reduction in gastric cancer incidence in Japan. Graduate School of Medicine *3 Department of Hematology, Toranomon Hospital *1FALCO biosystems Ltd. Tokai-chuo Laboratory *4 Department of Cancer Therapy Center, Fukui *2Department of Public Health and Occupational Prefectural Hospital Medicine, Mie University Graduate School of Medicine *5 Division of Cancer Epidemiology and Prevention, *3Division of Molecular Medicine, Aichi Cancer Center Miyagi Cancer Center Research Institute Research Institute *6 Center for Cancer Control and Statistics, Osaka Medical Center for Cancer and Cardiovascular Diseases *7Division of Surveillance, Center for Cancer Control

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).

2. The hospital-based epidemiologic *4Center for Genomic Medicine, Kyoto University research program at Aichi Cancer Center Graduate School of Medicine and Faculty of Medical

(HERPACC) study Sciences. *5 Department of Preventive Medicine, Kyushu 2.1. Impact of metallothionein gene University Faculty of Medical Sciences. polymorphisms on the risk of lung cancer in a Japanese population 2.2. Polymorphisms in CYP19A1, Ito, H.*1, Nakane, H.*2, Hirano, M.*3, Hosono, S., Oze, I., HSD17B1 and HSD17B2 genes and serum Matsuda, F.*4, Tanaka, H.*1, Matsuo, K.*5 sex hormone levels among Metallothioneins (MTs) are cysteine-rich proteins postmenopausal Japanese women .*1 *2, 3 that act as antioxidants. A case-control study was Hosono, S., Ito, H., Oze, I., Higaki, Y , Morita, E. , Takashima, N.*4, Suzuki, S.*5, Shimatani, K.*6, Mikami, conducted to assess the effects of gene *7 *8 *9 *10 polymorphisms in the MT region on the risk of lung H. , Ohnaka, K. , Ozaki, E. , Katsuura-Kamano, S. , Kubo, M.*11, Nagata, C.*12, Naito, M.*2, Hamajima, N.*13, cancer in Japanese subjects: 769 lung cancer cases Tanaka, H., and for the Japan Multi-Institutional and 939 non-cancer controls were included. Collaborative Cohort (J-MICC) Study Group. Associations were evaluated using logistic Extraovarian sex hormone production plays an regression models with adjustment for potential important role in estrogen biosynthesis in confounders (age, sex, and lifestyle factors postmenopausal women. We examined possible including smoking, drinking, and green-yellow associations between serum sex hormone level and vegetable intake). We found five polymorphisms in polymorphisms in CYP19A1, HSD17B1, and the MT-1 gene region that showed statistically HSD17B2. We also assessed possible interaction significant associations with lung cancer. Of these between these polymorphisms and current polymorphisms, rs7196890 showed the strongest overweight in a cross-sectional study. A total of 785 association (odds ratio: 1.30, P = 0.004, 95% Japanese naturally postmenopausal women were confidence interval: 1.09-1.55). The impact of the randomly selected from the Japan polymorphism decreased with increase of smoking, Multi-Institutional Collaborative Cohort (J-MICC) and virtually no association with lung cancer was study database. Information on lifestyle factors was observed among heavy smokers whose pack-year obtained from a self-administered questionnaire. values were 30 or more (odds ratio: 1.02, P = 0.93, Serum estrogens and androgens levels were 95% confidence interval: 0.67-1.55). These results measured by liquid chromatography–tandem mass suggest that polymorphisms in the MT gene are spectrometry. Four tag SNPs (single nucleotide moderately associated with the risk of lung cancer polymorphisms) of CYP19A1, one missense SNP of and that the associations are modified by lifestyle HSD17B1 and three tag SNPs of HSD17B2 were factors. examined by Invader assay. A trend test was conducted using linear regression. After adjustment *1Department of Epidemiology, Nagoya University for multiple comparisons, we found that rs4441215 Graduate School of Medicine *2 and rs936306 in CYP19A1 and rs4888202 and Social Systems Research Laboratory, Toyota Central rs2955160 in HSD17B2 were associated with R&D Labs., Inc. *3Environmental & Applied Biotechnology Laboratory, differences in serum estrone level. Further, Toyota Central R&D Labs., Inc.. rs4441215 and rs936306 were associated with

db SNP rs Number Estronea, b [mean±SD Estradiola, c [mean±SD Gene MAF number (n=785) (95%CI)] (pg/ml) (95%CI)] (pg/ml)

CYP19A1 Rs4441215 0.371 CC 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 0.402 CC 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 0.478 CC 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 differences in serum estradiol level. None of these *9Department of Epidemiology for Community Health polymorphisms showed any significant interaction and Medicine, Kyoto Prefectural University of Medicine with current body mass index (BMI). Our findings *10Department of Preventive Medicine, Institute of suggest that CYP19A1 and HSD17B2 Health Biosciences, The University of Tokushima polymorphisms might be associated with circulating Graduate School *11Laboratory for Genotyping Development, Center for sex hormone levels in Japanese postmenopausal Genomic Medicine, RIKEN, women, independent of current BMI. *12Department of Epidemiology and Preventive Medicine, Gifu University Graduate School of Medicine *1Laboratory of Exercise Physiology, Faculty of Sports *13Department of Healthcare Administration, Nagoya and Health Science University Graduate School of Medicine *2Department of Preventive Medicine, Nagoya University Graduate School of Medicine 2.3. Comparison of circulating miRNA *3Forestry and Forest Products Research Institute *4 levels between gastric cancer patients and Department of Health Science, Shiga University of non-cancer controls Medical Science Oze, I., Nagasaki, H.*1, Shimada, S.*1, Akiyama, Y.*1, *5Department of Public Health, Nagoya City University Hosono, S., Ito, H., Watanabe, M., Yatabe, Y.*2, Tanaka, Graduate School of Medical Sciences H., Matsuo, K.*3, Yuasa, Y.*1 *6Department of International Islands and Community Medicine, Kagoshima University Graduate School of Diffuse-type gastric cancer (DGC) exhibits a poor Medical and Dental Science prognosis and there are no effective serum *7Division of Cancer Registry, Prevention and biomarkers for early detection. Shimada et al. have Epidemiology, Chiba Cancer Center Research Institute established an E-cadherin/p53 double conditional *8Department of Geriatric Medicine, Kyushu University knockout (DCKO) mouse line, which recapitulates Graduate School of Medical Sciences human DGC morphologically and molecularly. We

8 identified three circulating miRNAs (miR-103, cohabitant with smoker, age at smoking initiation, miR-107, miR-194) as biomarkers of detecting motivation to quit smoking, self-efficacy of quitting early DGC using this DCKO mouse model. The smoking, the Center for Epidemiologic Studies purpose of this study was to evaluate the usefulness depression scale (CES-D), the Fagerström test for of the circulating miRNAs for the detection of nicotine dependence (FTND), strength of desire to human DGC. Subjects were first-visit outpatients at quit, previous abstinence, and varenicline use. Aichi Cancer Center Hospital. Cases were 50 Analysis of factors associated with maintained patients with DGC. Controls were age and sex cessation, which was defined as successful matched non-cancer outpatients. Lifestyle cessation at 3, 6 and 12 months after the SCT, in the information was collected by self-administered 550 abstainers at the end of SCT was subsequently questionnaire. Total RNA was extracted from the performed. plasma samples with miRNeasy Serum/Plasma Kit, Results: Having higher self-efficacy of quitting and then reverse-transcribed using an miScript II smoking (OR: 1.39, 95%CI: 1.06-1.82) and RT Kit. The levels of miRNAs in plasma samples varenicline use (OR: 2.48, 95% CI: 1.23-5.03) were were determined using an miScript SYBR Green associated with success of the SCT. Strong desire to Kit. Spiked-in cel-miR-39 was analysed as a smoke (OR: 0.67, 95%CI: 0.52-0.88) was a risk normalisation control.The three miRNA levels were factor for obstructing maintained cessation during not correlated with any clinical factors. The area the 12 months after the end of SCT. under the ROC curve (AUC) of miR-103, miR-107, Conclusion: Assessment of self-efficacy and miR-194 and the combination of three miRNAs strength of desire to smoke is important for were 0.55, 0.56, 0.51 and 0.62, respectively. The Japanese SCT participants. mean miRNA levels were not different between cases and controls. Thus plasma miR-103, miR-107 *1Department of Nursing, Sugiyama Jogakuen University and miR-194 levels do not appear to be useful *2Department of Respiratory Medicine, National Hospital biomarkers for detecting DGC. Organization Nagoya Medical Center *3 Department of Respiratory Medicine, National Hospital *1 Organization Kinki-Chuo Chest Medical Center Department of Molecular Oncology, Tokyo Medical *4 and Dental University Department of Respiratory Medicine, Japan *2 Community Healthcare Organization Chukyo Hospital Department of Pathology and Molecular Diagnostics, *5 Aichi Cancer Center Hospital Department of Respiratory Medicine, Kitasato *3 University Kitasato Institute Hospital Division of Molecular Medicine, Aichi Cancer Center *6 Research Institute Department of Chest Surgery, National Hospital Orgnaization Iwakuni Medical Center *7Department of Nursing, Nagoya University Graduate 3. Tobacco control School of Medicine

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, 9

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

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 several different origins has been investigated with novel negative regulator of RhoA respect to tumor genesis, progression and metastasis. associated kinase (ROCK) - is a critical However, its biological functions in tumor cells regulator of survival and growth of oral remain controversial. We established a critical role squamous carcinoma cells of CAR in growth regulation of oral squamous cell Saito, K., Sakaguchi, M.*1, Iioka, H., Matsui, M., carcinomas (SCCs) in vitro and in vivo via specific Nakanishi, H., Huh N.*1 and Kondo, E. interaction with Rho-associated protein kinase The Coxsackie and adenovirus receptor (CAR) (ROCK). In particular, loss of endogenous CAR is essential for adenovirus infection of target cells. expression by knockdown using a specific siRNA Constitutive expression in various cancer and facilitates growth suppression of SCC cells due to normal tissues has been reported and recently the cell dissociation, followed by apoptosis. The biological role of CAR in human neoplasms of 11 consequent morphological reaction appears Okayama University reminiscent of anoikis, rather than the epithelial-mesenchymal transition (EMT), and the 2. A extract of Cordyceps militaris inhibits dissociation of oral SCC cells appears to be angiogenesis and suppresses tumor triggered not by lack of contact with extracellular growth of human malignant melanoma cells matrix (ECM), but by loss of cell-to-cell contact Ruma IMW*1, Putranto EW*1, Kondo E, Watanabe R, Saito K, Inoue Y, Yamamoto K, Nakata S, Kaihata M, caused by abnormal translocation of E-cadherin *1 from surface membranes to cytoplasm. Murata H and Sakaguchi M . Angiogenesis is essential for tumor Immunoprecipitation assays of the CAR-transfected development and metastasis. Among several oral SCC cell line, HSC-2, with or without ROCK angiogenic factors, vascular endothelial growth inhibitor (Y-27632), revealed that CAR directly factor receptor (VEGF) is important for tumor associates with ROCKI and ROCKII, resulting in angiogenesis and is commonly overexpressed in inhibition of ROCK activity and contributing to solid tumors. Thus, many antitumor strategies maintenance of cell-to-cell adhesion for growth and targeting VEGF have been developed to inhibit survival. Based on these findings, in vivo behavior cancer angiogenesis, offering hope successful of CAR-downregulated HSC-2 cells from siRNA treatment of solid cancers. However, there are a knockdown was compared with that of normally number of issues such as harmful effects on normal CAR-expressing cells in intraperitoneally vascularity in clinical trials. Taking this into xenografted mouse models. We found that mice consideration, we employed Cordyceps militaris as engrafted with CAR siRNA-pretreated HSC-2 cells an antitumor approach due to its biological safety in showed poor formation of metastatic foci in vivo. The herbal medicinal mushroom Cordyceps contrast to those implanted with control militaris has been reported to show potential siRNA-pretreated cells that maintained endogenous anticancer properties including anti-angiogenic CAR expression and that disseminated extensive capacity; however, its concrete properties have yet peritoneal lesions. Thus, CAR substantially impacts to be fully demonstrated. In this study, we aimed to on growth and survival of oral SCC cells through elucidate the biological role of Cordyceps militaris specific interactions with ROCK in vitro and in extract in tumor cells, especially in regulating vivo, providing clues for the molecular therapy or angiogenesis and growth of a human malignant head and neck SCCs. *1 Department of Cell Biology, Graduate School of melanoma cell line. We demonstrated the Medicine, Dentistry and Pharmaceutical Sciences, 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, Fig. 1. Schematic representation of biological Okayama University effects of CAR (Coksackie and adenovirus *2 Division of Cancer Biology, The Cancer Institute of receptor) on Rho A-associated kinase. Moderate the Japanese Foundation for Cancer Research (JFCR) suppression of ROCK activity by CAR facilitates *3 Department of Tumor Immunology, Aichi Medical growth, invasion and metastasis of SCC cells. University School of Medicine This work was published in “Oncogene” March *4 Department of Respiratory Medicine, Okayama 18, 2013. University Hospital

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. 3. Development of a New Rapid Isolation militaris (n=3, mean volume 384 mm3 on day 37); Device for Circulating Tumor Cells (CTCs) *P=0.069 >0.05. Final masses of tumors excised on using 3D Palladium Filter and its day 37 in each group are also shown in the graph Application for Genetic Analysis (right). Saline (n=3, mean weight of 874 mg) vs. C. Yusa A, Toneri T, Masuda T, Ito S, Yamamoto S, Okochi militaris (n=3, mean weight of 230 mg); **P=0.031 M, Kondo N, Iwata H, Yatabe Y, Ichinosawa Y, Kinuta S, <0.05. Means and SE (standard error) of triplicates Kondo E, Honda H, Arai F, Nakanishi H. are shown. Circulating tumor cells (CTCs) in the blood of patients with epithelial malignancies provide a recovery rate of tumor cells from blood with this Pd promising and minimally invasive source for early filter device was more than 85%. Single living detection of metastasis, monitoring of therapeutic tumor cells were efficiently isolated from spiked effects and basic research addressing the tumor cells by a micromanipulator, and KRAS mechanisms of metastasis. In this study, we mutation, HER2 gene amplification and developed a new filtration-based, sensitive CTC overexpression, for example, were successfully isolation device, consisting of a 3-dimensional (3D) detected from such isolated single tumor cells. palladium (Pd) filter with an 8 μm-sized pore in the Sequential analysis of blood from mice bearing lower layer and a 30 μm-sized pocket in the upper metastases revealed that CTC increased with layer to trap CTCs on a filter micro-fabricated by progression of metastasis. Furthermore, a precise lithography plus electroforming processes. significant increase in the number of CTCs from the This simple pump-less device driven by gravity blood of patients with metastatic breast cancer was flow can enrich CTCs from whole blood within 20 observed compared with patients without metastasis min. After on-device staining of CTCs for 30 min, and healthy volunteers. These results suggest that the filter cassette was removed from the device, this new 3D Pd filter-based device could be a useful fixed in a cassette holder and set up on an upright tool for rapid, cost effective and sensitive detection, fluorescence microscope. Enumeration and enumeration, isolation and genetic analysis of CTCs isolation of CTCs for subsequent genetic analysis from peripheral blood in both preclinical and were completed within 1.5 hr and 2 hr, respectively. clinical settings. Cell spike experiments demonstrated that the

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.

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 Fig. 4. Multimodality imaging with combination to detect by conventional computed tomography of 3D optical imaging and MRI for peritoneal (CT) and magnetic resonance imaging (MRI) at an metastases. Multimodality images constructed early stage. To improve the sensitivity and by fusion of optical and MRI images. specificity of diagnostic imaging for peritoneal This work was publicshed in Gastric Cancer metastases, here, we developed a new type of 173(3), 497-507. 2014 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

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

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.

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 Fig. 1. (a) BAP1 gene mutations in MM cell lines. both inhibition of cell proliferation and The five cell lines (Y-MESO-9, 14, 25, and 61, anchorage-independent cell growth of MM cells and ACC-MESO-4) were established in our lab, with BAP1-deletion, while BAP1 mutants of a and two (NCI-H28 and H2452) were kindly missense or C-terminal truncated form showed only provided from Dr. Adi F. Gazdar. partial or no growth inhibitory effects. Next, we (b) BAP1 mutation effects on its own nuclear studied whether or not BAP1 is involved in MM localization. Immunofluorescence analysis of cell survival after DNA damage. After irradiation subcellular BAP1 localization was performed (IR), we detected that both wild-type and mutant after transduction of BAP1 vectors, and BAP1 were similarly phosphorylated and percentages of subcellular localization of BAP1 phospho-BAP1 was localized mainly in the nucleus. were calculated. Interestingly, BRCA1 proteins were decreased in the MM cells with BAP1 deletion, and that 2. SMC2 regulates the transcription of transduction of the mutants as well as wild-type DDR genes and shows synergistic BAP1 increased BRCA1 proteins, suggesting that phenotype with MYCN BAP1 may promote DNA repair partly through the Murakami-Tonami, Y., Kishida, S.*1, Takeuchi, I.*2, stabilization of BRCA1 protein. Additionally, using Katou, Y.*3, Maris, JM.*4, Ichikawa, H.*5, Kondo, Y.*6, *3 *7 the MM cells with BAP1 deletion, we found that Sekido, Y., Shirahige, K. , Murakami, H. , and *1 the wild-type, and even a missense mutant, BAP1 Kadomatsu, K. conferred a higher survival rate after IR compared The condensin complex is required for to the control vector. Our results indicated that, chromosome condensation during mitosis. It has while wild-type BAP1 suppresses MM cell been reported that condensin complex also has a proliferation and restores cell survival after role in interphase, but it is still not clear about its IR-damage, some mutant BAP1 may also role in interphase compared to mitosis. moderately retain these functions. Neuroblastoma is the most common extracranial childhood tumor of sympathetic neuron. In human *1Department of Thoracic Surgery, Nagoya University neuroblastoma, MYCN amplification correlates Graduate School of Medicine, Nagoya, Japan with poor prognosis. Here we found that downregulation of SMC2 (structural maintenance of chromosome 2), condensin complex subunit, and MYCN amplification/overexpression showed synergistic

17 lethal response in human neuroblastoma cells. *1Department of Molecular biology, Nagoya University SMC2 knockdown in MYCN Graduate School of Medicine amplified/overexpressed neuroblastoma cells *2Department of Computer Science/Scientific and Engineering Simulation, Nagoya Institute of Technology induced DNA damage, leading to apoptosis. In *3 addition, we showed that SMC2 interacts MYCN Laboratory of Genome Structure & Function, Institute of Molecular and Cellular Biosciences, The University of and transcriptionally regulates DNA damage Tokyo response (DDR) genes. Finally we showed that *4Department of Pediatrics and Center for Childhood patients bearing MYCN amplified tumors tend to Cancer Research, Children's Hospital of Philadelphia, benefit from low SMC2 expression. Our results University of Pennsylvania identify novel function of SMC2 (or condensin *5Division of Genetics, National Cancer Institute complex) in DDR and we proposed that SMC2 or *6Department of Epigenomics, Nagoya City University condensin complex is a potential molecular target Graduate School of Medical Sciences *7 of MYCN-amplified neuroblastoma. Department 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.

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.

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 stratified by a combination of ALDH2 genotype upper-aerodigestive tract cancer using and alcohol consumption to aid the development of molecular and environmental information personalized prevention. We conducted two age- Koyanagi, Y.*1, Ito, H.*2, Oze, I.*2, Hosono, S.*2, and sex- matched case-control studies, one (630 Watanabe, M.*2, Tanaka, H.*2, Abe, T.*3, Shimizu, Y.*3, cases and 1,260 controls) for model derivation and Hasegawa, Y.*4, and Matsuo, K. the second (654 cases and 654 controls) for external Alcohol consumption and aldehyde validation. Based on data from the derivation study, dehydrogenase 2 (ALDH2) polymorphisms are a prediction model was developed by fitting a associated with upper-aerodigestive tract (UATC) conditional logistic regression model using the risk, and a significant gene-environment interaction following predictors: age, sex, smoking, drinking, between the two has been confirmed in various and ALDH2 genotype. The risk model, including a studies in Asia. We have developed a risk combination of ALDH2 genotype and alcohol prediction model and estimated absolute risks consumption, provided high discriminatory

20 accuracy and good calibration in both the derivation singly-transduced with either Card11L232LI or and validation studies: C statistics were 0.82 (95% Bcl6 died during the same period of time. The confidence intervals 0.80–0.84) and 0.83 developed lymphomas expressed exogenously (0.81–0.85), respectively, and calibration plots of expressed Card11L232LI and Bcl6, and both studies stayed close to the ideal calibration line. endogenous Irf4, which is a molecular hallmark of Cumulative risks were obtained by combining odds activated B cell-like DLBCL, the most aggressive ratios estimated from the risk model with the subtype of DLBCL. These mouse models may help age-specific incidence rate and population size. For elucidate the molecular mechanisms underlying B heavy drinkers with a heterozygous genotype, cell neoplasms and may aid in the development of cumulative risk at age 80 was above 20%. In effective therapeutic drugs. contrast, risk in the other groups was less than 5%. In conclusion, modification of alcohol consumption *1Third Department of Internal Medicine, Graduate according to ALDH2 genotype will have a major School of Medicine and Pharmaceutical Sciences, impact on UATC prevention. These findings University of Toyama, Toyama, Japan *2 represent a simple and practical model for Department of Pathology, School of Medicine, Kurume University, Kurume, Japan personalized cancer prevention.

*1Department of Preventive Medicine, Kyushu 3. Establishment of a new mouse model of University Faculty of Medical Sciences, Fukuoka, Japan adult T cell leukemia *1 *1 *2Division of Epidemiology and Prevention, Aichi Kasugai-Maeda, Y., Yoshida, N. , Seto, M. , and Cancer Center Research Institute, Aichi, Japan Tsuzuki, S. *3Department of Gastrointestinal Surgery, Aichi Cancer Acute type adult T-cell leukemia (acute ATL) Center Central Hospital, Aichi, Japan develops in human T-cell leukemia virus type 1 *4Department of Head and Neck Surgery, Aichi Cancer (HTLV-1) carriers. Although the HTLV-1-encoded Center Central Hospital, Aichi, Japan HBZ gene is critically involved, HBZ alone is Division of Molecular Medicine insufficient, and cooperative additional “hits” are required for the development of ATL. Candidate 2. Generation of mouse models of cooperative hits are being delineated, but methods lymphoid neoplasms using retroviral gene to rapidly explore their roles in ATL development in transduction of in vitro-induced germinal collaboration with HBZ are lacking. We present a center B cells new mouse model of rapidly generated acute ATL Takahara T., Arita, K.*1, Yoshida, N.*2, Sugiyama, T.*1, that features transplanting in vitro-induced T cells *2 Seto, M. , and Tsuzuki, S. retrovirally transduced with HBZ, and two Evidence is accumulating that hematologic cooperative genes BCLxL and AKT, into mice. T malignancies develop following acquisition of cells co-transduced with HBZ/BCLxL/AKT multiple genetic changes. Because of the allowed in vitro-generated T cells to grow in the complexity of these genetic changes, the generation absence of cytokines (Flt3-ligand and IL-7), which of animal models is often laborious. In an effort to was not attainable with the use of any combination circumvent this difficulty, we previously established of the two genes. Upon transplantation into mice, a mouse model by employing in vitro-induced although transplanted T cells were a mixture of mouse germinal center (GC) B cells; the GC B cells cells variously transduced with the three genes, the were induced in vitro, retrovirally transduced with a tumors developing in the animals were composed of combination of genes or mutated genes of interest, HBZ/BCLxL/AKT-triply transduced T cells, and transplanted into mice. Using this model showing synergistic activity of the three genes. system, we were able to generate diffuse large B The genetic/epigenetic landscape of ATL has only cell lymphoma (DLBCL) by a combination of Myc recently been elucidated, and actual roles of the and Bcl2. We also found that a combination of elucidated “hits” in ATL pathogenesis remain to be Burkitt lymphoma-associated genes Myc, explored. Our model thus is important in providing CCND3T283A, E47V557E, Akt and TCL1A a versatile tool to explore roles of the hits in the induced Burkitt-like lymphoma, and that a development of acute ATL, in collaboration with combination of Card11L232LI and Bcl6 induced HBZ. DLBCL in mice. All mice receiving a transplant of Card11L232LI/Bcl6 co-transduced GC B cells died *1Department of Pathology, School of Medicine, Kurume or developed lymphoma within two months after University, Kurume, Japan transplantation, while none of a group of mice receiving a transplant of GC B cells 4. Clonal heterogeneity of lymphoid

21 malignancies correlates with poor K.*1, Yoshida, N.*2, Karube, K.*3, Katayama, M., prognosis Nakanishi, H.*4, Kiyono, T.*5, Nakamura, S.*6, Osada, Katayama, M., Yoshida, N., Umino A.*1, Kato H.*2, H.*7, Sekido, Y.*7, Seto, M.*2,8, and Tsuzuki, S. Tagawa, H.*3, Nakagawa, M.*4, Fukuhara, N.*5, Disruption of the Hippo pathway as a result of Sivasundaram, S.*6, Takeuchi, I.*7, Hocking TD.*8, Arita, deletion and/or mutation of the involved genes (e.g., K., Karube, K., Tsuzuki. S, Nakamura, S.*9, Kinoshita neurofibromin 2 [NF2]) is frequently observed in T.*2, and Seto, M. mesothelioma. The disruption results in reduced Clonal heterogeneity in lymphoid malignancies phosphorylation of yes-associated protein (YAP), has been recently reported in adult T-cell the non-phosphorylated YAP translocating to the lymphoma/leukemia, peripheral T-cell lymphoma, nucleus and regulating gene expression. While roles not otherwise specified, and mantle cell lymphoma. of the disrupted Hippo pathway in maintenance of We have extended analyses to other types of established tumors have been investigated using lymphoma including marginal zone lymphoma, mesothelioma cell lines, involvement in the follicular lymphoma, and diffuse large B-cell initiation of mesothelioma development remains lymphoma. To determine the presence of clonal unclear.We have employed immortalized human heterogeneity, 332 cases were examined using array mesothelial cells to study the transformation comparative genomic hybridization analysis. process, and found that NF2 knockdown led to Results showed that the incidence of clonal transformation of the cells concurrently with heterogeneity varied from 25% to 69% among reduction in YAP phosphorylation. The targeted different types of lymphoma. Survival analysis cells exhibited enhanced growth in vitro, and revealed that mantle cell lymphoma and diffuse formed tumors following transplantation into nude large B-cell lymphoma with clonal heterogeneity mice. Similar results to those obtained by NF2 showed significantly poorer prognosis, and that knockdown were also achieved using forced clonal heterogeneity was confirmed as an expression of wild-type (wt) or constitutively active independent predictor of poor prognosis for both (S127A) YAP. Although such directed expression of types of lymphoma. Interestingly, 8q24.1 (MYC) YAPwt or YAPS127A was insufficient to transform gain, 9p21.3 (CDKN2A/ 2B) loss and 17p13 (TP53, primary (unimmortalized) human mesothelial cells, ATP1B2, SAT2, SHBG) loss were recurrent our findings provide evidence for crucial roles of genomic lesions among various types of lymphoma activated YAP in transformation of mesothelial cells. with clonal heterogeneity, suggesting at least in part To identify YAP-regulated genes critical for that alterations of these genes may play a role in mesothelial tumorigenesis, we conducted gene clonal heterogeneity. expression analysis comparing control- and YAP-transduced immortalized human mesothelial *1Department of Hematology and Oncology, Mie cells. Gene Set Enrichment Analysis (GSEA) using University Graduate School of Medicine *2 a gene set down-regulated by YAP knock-down in Department of Hematology and Cell Therapy, Aichi mesothelioma cell lines revealed phospholipase C Cancer Center hospital, Nagoya, Japan; *3Department of Hematology, Nephrology, and beta 4 (PLCB4) to be among the top-ranking genes Rheumatology, Akita University Graduate School of up-regulated by YAP in our experiments. PLCB4 Medicine, Akita, Japan was up-regulated by YAP in immortalized human *4Lymphoid Malignancies Branch, Center for Cancer mesothelial cells, and down-regulated by YAP Research, National Cancer Institute, USA knock-down in YAP-driven mesothelioma cells. *5Department of Hematology and Rheumatology, Tohoku shRNA-mediated silencing of PLCB4 attenuated University Hospital, Sendai, Japan the growth of YAP-transduced mesothelial cells and *6Department of Biochemistry, Aichi Medical University Hippo-disrupted, but not -proficient, mesothelioma School of Medicine, Nagakute, Japan *7 cell lines. Department of Computer Science/Scientific and Our model system thus provides a versatile tool Engineering Simulation, Nagoya Institute of Technology, Nagoya, Japan to investigate mechanisms underlying *8Department of Human Genetics, McGill University, mesothelioma development. We suggest that Montréal, Canada; PLCB4 may be an attractive drug target for *9Department of Pathology and Clinical Laboratories, treatment of malignant mesothelioma. Nagoya University Hospital, Nagoya, Japan *1Third Department of Internal Medicine, Graduate 5. Establishment of a model of YAP-driven School of Medicine and Pharmaceutical Sciences, malignant mesothelioma University of Toyama, Toyama, Japan *2 Kakiuchi, T., Takahara, T., Kasugai-Maeda, Y., Arita, Department of Pathology, School of Medicine, Kurume University, Kurume, Japan 22

*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

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

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.

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 *1Department of Gynecologic Oncology, Aichi Cancer HLA-Cw7-binding peptide that cross-reacts Center Hospital *2 with HLA-A24-restricted ovarian Department of Obstetrics and Gynecology, Nagoya cancer-specific CTLs University Graduate School of Medicine Demachi-Okamura, A., Yamada, E., Kondo, S.*1, Shibata, K.*2, Kikkawa, F.*2, and Kuzushima, K. 2. Interaction of V α 24 iNKT cells with Cytotoxic T lymphocytes (CTLs) can exert dendritic cells increases the therapeutic anti-tumor effects through recognition of tumor efficacy of TCR-gene modified T cells antigen-derived peptides bound to human leukocyte Zhang, R., Uemura, Y.*1, Liu, T.*2, Ikeda, H.*3, Okamoto, antigens (HLAs) on cell surfaces. This recognition S.*4, Tatsumi, M., Mineno, J.*4, Shiku, H.*3, and activates T-cell receptors (TCR). CTLs to probe Kuzushima, K. such peptides are important reagents to define Adoptive immunotherapy using TCR tumor antigens but generating tumor-specific CTLs gene-modified T cells is an attractive strategy for usually requires autologous tumor cell lines. We targeting cancer. Human telomerase reverse have successfully induced cancer-specific CTLs transcriptase (hTERT) is a promising target antigen using artificial antigen presenting cells (aAPCs) for cancer immunotherapy due to its expression in that have endogenous tumor-associated peptides on vast majority of human tumors. We previously given HLA molecules but not their own HLAs. established a HLA-A24-restricted and We report here an HLA-A24-restricted CTL hTERT461-469-specific T cell clone and demonstrated clone, which was established from naïve CD8+ T the utility of the T cell epitope for cancer lymphocytes stimulated with aAPCs derived from immunotherapy (Int J Cancer 110: 403-412). In the current study, TCRα/β genes from this T cell clone TOV21G, an ovarian cancer cell line. The CTL + clone responded not only to ovarian cancer cells in were transduced with CD8 T cells and their the context of HLA-A24 but also to allogeneic anti-tumor potential was analyzed. The redirected T HLA-Cw7 molecules through cross-reactive TCR cells efficiently expressed the transduced TCRs and recognition. Using the cDNA expression cloning killed hTERT peptide-loaded T2-A24 cells, but method, the CTL clone alloreacted, this being never exhibited cytotoxicity against lung cancer mediated through a nine-mer peptide derived from cells expressing both HLA-A24 and hTERT. To the TOV21G cellular protein, RBM4. The epitope address this issue, we used invariant NKT (iNKT) peptide presented by HLA-A24 cells has yet to be cells, a unique subset of T cells that recognize identified. The CTL was demonstrated to be α-GalCer presented by CD1d on antigen-presenting monoclonal on account of single positivity in cells, as a cellular adjuvant. We found that soluble tetramer staining, indicating that the factors from the iNKT cell/α-GalCer-dendritic cell HLA-A*24:02-restricted tumor-specific clone (DC) interaction enhanced the HLA-I expression on recognizes the epitope peptide presented by cancer cells, thereby increasing susceptibility to cell allo-HLA-Cw*07:02 in a cross-reactive manner. lysis. In addition, the soluble factors upregulated Moreover, the clone showed a requirement for both perforin and granzyme B in redirected T cells, peptides presented by HLA-Cw7 and the specificity in turn enhancing the potency of cellular immunity. for peptides was vague, implying that the TCR Furthermore, in vivo transfer of redirected T cells in featured polyspecific alloreactivity. combination with iNKT/α-GalCer-DC inhibited To our knowledge, these results provide the first tumor growth and significantly prolonged survival evidence of allorecognition of an HLA-Cw allele by in a xenograft model. Thus, the additional transfer HLA-A-restricted T-cells. They suggest of iNKT/α-GalCer-DC may improve the efficacy of allorecognition in certain HLA combinations, and redirected T cells. further study is now needed to understand the *1 mechanisms of alloreactivity to improve the Division of Cancer Immunotherapy, Exploratory prediction of alloresponses in clinical settings. Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa. *2Cancer Center, Chinese PLA General Hospital., Beijing, 26

China. cancer cells highly-sensitive to anti-cancer *3Department of Immuno-Gene Therapy, Mie University drugs through DNA damage Graduate School of Medicine, Mie. Gondo, N., Rezano A.*1, Ohta, R., Kuzushima, K., *4Center for Cell and Gene Therapy, Takara Bio Inc., Toyama, T.*2, and Kuwahara, K. Shiga. Breast cancer is a leading cause of cancer death of women all over the world. Genetic BRCA1/2 3. Cellular adjuvant properties and direct insufficiency is associated with breast cancer cytotoxicity in rejuvenated Vα24 invariant development, but germline mutations of the two NKT cells from human induced pluripotent genes have been only rarely observed in sporadic stem cells breast cancers, which account for approximately Zhang, R., Kitayama, S.*1, Liu, R.*2, Ueda, N., Tatsumi, *1 *3 95% of the total. Some reports have indicated that M., Kaneko, S. , Kuzushima, K., and Uemura, Y. overexpression of BRCA2 significantly correlate Vα24 invariant natural killer T (iNKT) cells are with poor survival and worse histological findings; a small subset of T lymphocytes implicated in the however, the contribution of BRCA2 to regulation of a broad range of immune responses. tumorigenesis or malignant progression in sporadic They recognize specific lipid antigens presented by breast cancers still remains controversial. CD1d on antigen-presenting cells and induce both DSS1 (deleted in split-hand/split-foot innate and adaptive immune responses. Their malformation 1), a mammalian component of the powerful adjuvant properties, which enhance transcription/mRNA export complex, has been effective immunity against cancer, means that they shown to interact with and stabilize BRCA2. We represent promising therapeutic tools. However, this initially investigated the expression level of DSS1 has been hampered by the difficulty of preparing mRNA using 289 samples derived from patients functional iNKT cells from patients in large enough with sporadic breast cancers, and classified into numbers to be therapeutic. To overcome this DSS1high and DSS1low groups. Although no obstacle, we used Yamanaka factors to reprogram significant differences were observed between the human iNKT cells to pluripotency and then groups for several parameters such as nodal status regenerated Vα24 invariant, TCR-expressing T and nuclear grade, the DSS1high group showed a lymphocytes in vitro through optimized α-chain significant shorter survival in relapse-free survival cytokine combination. Like the parental iNKT cells, curves, while the difference in the breast the regenerated iNKT (re-iNKT) cells showed cancer-specific survival curve was not significant. γ proliferation and IFN- production in response to These results were supported by the public database α-galactosylceramide (α-GalCer). The re-iNKT of Kaplan-Meier, designated KMplotter. cells also induced dendritic cell maturation and In order to clarify the significance of DSS1 downstream activation of cancer antigen-specific levels in patient prognosis, in vitro studies using cytotoxic T lymphocytes in vitro, and exhibited DSS1-overexpressed and -knockdown breast cancer NKG2D- and DNAM-1-mediated natural killer cells were performed. DSS1-overexpressed cells cell-like cytotoxicity against cancer cell lines. In did not show any proliferative changes, but became addition to their availability in an unlimited supply more resistant to chemotherapy. On the other hand, from induced pluripotent stem cells, the cellular DSS1-depletion increased chemosensitivity. A adjuvant properties and a newly identified cytotoxic similar phenotype was also observed using feature of these re-iNKT cells offer the potential for camptothecin, etoposide, doxorubicin, paclitaxel, development of effective immunotherapies against and cisplatin. DSS1 has some binding partner such cancer. as BRCA2, 26S proteasome subunits, and TREX2

*1 component PCID2. Shin Kaneko Laboratory, Department of Cell Growth We speculated that increased chemosensitivity and Differentiation, Center for iPS cell Research and by DSS1 depletion might be affected by BRCA2 Application (CiRA), Kyoto University, Kyoto. *2Cancer Center, Chinese PLA General Hospital., Beijing, insufficiency; however, BRCA2 knockdown China. showed marginal effects on chemosensitivity. This *3Division of Cancer Immunotherapy, Exploratory result indicates that DSS1 depletion confers a drug Oncology Research & Clinical Trial Center, National sensitive trait for anti-cancer chemotherapy Cancer Center, Kashiwa. independently of BRCA2.

4. Depletion of DSS1, which is a member *1Department of Anatomy and Cellular Biology, of mammalian TREX2 complex and Universitas Padjadjaran, Bandung, Indonesia. maintains BRCA2 stability, confers breast *2Department of Oncology, Immunology and Surgery,

Nagoya City University Graduate School of Medical Sciences.

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

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 activation was required for tumorigenesis and controls cancer progression invasiveness in some cancer cells featuring c-Src Oneyama, C., Kuwahara, A., Miyata, M., and Watanabe, upregulation. We propose that the Src–Fer axis R. represents a new therapeutic target for treatment of c-Src is upregulated in various human cancers, a subset of human cancers. suggesting roles in development and progression of malignancies. However, the molecular circuits of 2. MicroRNA-mediated gene expression c-Src oncogenic signaling remain elusive. We have controls Src-related oncogenic signaling shown that a Fer tyrosine kinase oligomer mediates Oneyama, C., Ninomiya, Y., Miyata, M., and Watanabe, and amplifies Src-induced tumor progression. R. Previously, we found that transformation of The cellular Src (c-Src) tyrosine kinase is fibroblasts is promoted by the relocation of c-Src to upregulated and believed to play a pivotal role in non-raft membranes. Under these conditions, we various human cancers. However, the molecular identified Fer and ezrin as non-raft c-Src targets. mechanisms underlying c-Src-mediated tumor c-Src directly activated Fer by initiating its progression remain elusive. Recent studies have autophosphorylation, which was further amplified revealed that several microRNAs (miRNAs) by Fer oligomerization. Fer interacted with active function as tumor suppressors by regulating the c-Src at focal adhesion membranes and activated malignancy-associated expression of signalling Fer-phosphorylated ezrin to induce cell molecules. Aberrant expression of miRNAs is transformation. Fer also proved crucial for cell frequently observed in human cancers and should transformation induced by v-Src or epidermal be exploited to seek related molecular targets. We growth-factor receptor activation. Furthermore, Fer have focused on miRNAs found to be involved in 30

Src signalling in various cancers. 3. Clustered microRNAs of the Epstein- We found that among the c-Src-regulated Barr virus cooperatively downregulate an microRNAs (miRNAs), miR-27b is also repressed epithelial cell-specific metastasis by activation of K-Ras ⁄ H-Ras. Inhibitor studies suppressor suggested that the phosphatidylinositol 3-kinase Kanda, T., and Miyata, M. pathway is involved in the repression of miR-27b, a The Epstein-Barr virus (EBV) encodes its own characteristic of various colon cancer cell lines and microRNAs (miRNAs); however, their biological tumor tissues. Re-expression of miR-27b in human roles remain elusive. The commonly used EBV colon cancer HCT116 cells caused morphological B95-8 strain lacks a 12-kb genomic region, known changes and suppressed tumor growth, cell as the BamHI A rightward transcripts (BART) adhesion, and invasion. We also identified locus, where a number of BART miRNAs are ARFGEF1 and paxillin as novel targets of miR-27b, encoded. Here, bacterial artificial chromosome and established that miR-27b-mediated regulation (BAC) technology was used to generate an EBV of ARFGEF1 is crucial for controlling B95-8 strain in which the 12-kb region was fully anchorage-independent growth. We could further restored at its native locus [BART(+) virus]. show that paxillin is important for controlling cell Epithelial cells were stably infected with either the adhesion and invasion. Re-expression of miR-27b parental B95-8 virus or the BART(+) virus, and suppressed the activation of c-Src induced by BART miRNA expression was shown to be integrin-mediated cell adhesion, suggesting that successfully reconstituted in the BART(+) repression of miR-27b may contribute to c-Src virus-infected cells. Microarray analyses of cellular activation in cancer cells. gene expression identified N-myc downstream These findings provide strong evidence that regulated gene 1 (NDRG1) as a putative target of miR-27b functions as a tumor suppressor by BART miRNAs. The NDRG1 protein was barely controlling ARFGEF1 and the paxillin ⁄ c-Src expressed in B cells, highly expressed in epithelial circuit at focal adhesions. Thus, we continue our cells, including primary epithelial cells, and focus on Src-related miRNAs, their target genes, strongly downregulated in BART(+) virus-infected mechanisms behind their interplay and their epithelial cells of various origins. Although in vitro implications for cancer therapeutics. 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 Fig. 1. When active c-Src is liberated from lipid expression and epithelial carcinogenesis in vivo. 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. 31

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.

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

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 by PCR for sequencing, followed by identification HNRNPLL as a novel colorectal cancer of the candidate genes targeted by the shRNA. metastasis suppressor Among 47 candidate genes identified, we focused Sakuma, K., Sasaki, E., Kimura, K., Komori, K., on Hnrnpll (heterogeneous nuclear Shimizu, Y., Yatabe, Y., and Aoki, M. ribonucleoprotein L-like) gene encoding a Despite the recent advances in treatment of pre-mRNA binding protein involved in pre-mRNA colorectal cancer, the prognosis is unfavorable for splicing. Hnrnpll knockdown in CMT93 cells patients with distant metastases. With an attempt to significantly increased their matrigel invasion in identify novel targets for prevention and/or therapy vitro and lung metastasis in vivo, which could be of colorectal cancer metastasis, we performed a cancelled by introducing an shRNA-resistant functional in vivo shRNA library screen for Hnrnpll cDNA. Interestingly, an metastasis suppressor genes using an orthotopic RNA-immunoprecipitation analysis identified Cd44 transplantation model. CMT93 cells, a murine as a candidate target of Hnrnpll, and the mRNA colorectal cancer cell line with poor metastasizing level of Cd44 variant 6 (Cd44v6), a splicing variant activity, were transduced with Venus fluorescent of Cd44 that had been shown to demarcate colon protein and lentiviral shRNA library, and then cancer stem cells driving colon cancer metastasis, transplanted into the rectum of C57/BL6 mice. was increased by knocking down Hnrnpll in colon Genomic DNA was collected from metastatic cancer cells. Furthermore, treatment with lesions, and the integrated shRNA were retrieved anti-CD44v6 monoclonal antibody suppressed 34 matrigel invasion of colon cancer cells induced by suppression sensitizes them to EGFR inhibition. Hnrnpll knockdown in vitro, suggesting that Our findings may provide a rationale for Hnrnpll may suppress invasion and metastasis, at combination therapy with EGFR inhibitors and least in part, by modulating the alternative splicing mTOR kinase inhibitors for colon cancer patients. of Cd44. To gain further insights into the involvement of HNRNPLL in colorectal cancer *1Department of Pharmacology, Graduate School of invasion and metastasis, we examined its Medicine, Kyoto University expression during epithelial-mesenchymal transition (EMT), and found that EMT induction 3. The MEK/ERK signaling inhibition reduced the HNRNPLL level in SW480 cells. The suppresses intestinal polyp formation by link between HNRNPLL and EMT was further reducing the stromal COX-2 and CCL2 suggested by immunostaining analysis of clinical levels samples; colorectal cancer cells with low Fujishita, T., Kajino, R., Kojima, Y., Taketo, MM.*1, and

E-cadherin expression at the invasion front Aoki, M. exhibited decreased HNRNPLL expression as Frequent mutations in the KRAS gene in colon compared with those in the tumor center. These cancer suggest that inhibition of the MEK/ERK results suggest that HNRNPLL is a novel metastasis signaling can benefit colon cancer patients. suppressor in colorectal cancer. However, the precise roles of the signaling in intestinal tumor formation remain to be elucidated. 2. Simultaneous inhibition of mTOR and We found that the MEK/ERK signaling was EGFR suppresses invasion of intestinal frequently activated in stromal cells, such as adenocarcinoma in cis-Apc+/Δ716 Smad4+/- vascular endothelial cells and fibroblasts, rather than in adenoma epithelial cells in intestinal polyps mice Δ716 Fujishita, T., Kojima, Y., Kajino, R., Taketo, MM.*1, and of Apc mice. Treatment with the MEK inhibitor Aoki, M. trametinib suppressed intestinal polyp formation, Activation of the mechanical target of accompanied by reduced adenoma cell proliferation rapamycin (mTOR) signaling is implicated in and angiogensis. Trametinib treatment reduced the various human cancers. We previously reported that cyclooxgenase-2 (COX-2) level both in primary Δ716 activation of mTOR complex 1 (mTORC1) was cultures of intestinal fibroblasts and in Apc required for expansion of adenomatous polyps that polyps. Moreover, the level of chemokine (C-C developed in the intestines of Apc+/ △ 716 mice. motif) ligand 2 (CCL2), a chemokine implicated in However, the roles of the mTOR signaling in formation of Apc mutant polyps, was reduced in invasive intestinal adenocarcinomas have remained fibroblasts treated in vitro with trametinib or the elusive. Treatment of cis-Apc+/ △ 716/Smad4+/– COX-2 inhibitor rofecoxib, as well as in the polyps of trametinib-treated ApcΔ716 mice. These results (cis-Apc/Smad4) mice, a mouse model of suggest that the stromal MEK/ERK signaling locally-invasive intestinal adenocarcinoma, with the promotes intestinal polyp expansion through mTORC1 inhibitor everolimus significantly production of COX-2, which can up-regulate the suppressed expansion of their tumors. Moreover, pro-inflammatory chemokine CCL2. the ATP-competitive mTOR kinase inhibitor

AZD8055 suppressed the growth of intestinal *1Department of Pharmacology, Graduate School of adenocarcinomas more potently than everolimus. Medicine, Kyoto University 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 Fig.1. Schematic representation of the roles of resistance of invasive intestinal adenocarcinomas the stromal MEK/ERK signaling in intestinal against mTOR inhibition in vivo, and that mTOR adenoma formation in Apc mutant mice. 35

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 Apc Δ 716 mice using confocal lase scanning microscopy. Nuclei are stained with DAPI (blue).

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

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 reassembly is suppressed by trichoplein-mediated assembly Aurora-A activation in growing cells. We found that Inaba, H., Goto, H., Kasahara, K., Inoko, A., He, D., Ndel1, a well-known modulator of dynein activity, Tanigawa, N., Hayashi, Y., Kobori, K., Kumamoto, K.*1, localizes at the subdistal appendage of the mother Yonemura, S. *2, Goshima, N.*3, Yamano S.*4, Wanibuchi, centriole, which nucleates a primary cilium. In the *4 *5 *1 H. , Kiyono, T. , Hirotsune, S. , and Inagaki, M. presence of serum, Ndel1 depletion reduced The primary cilium projects from cell surfaces trichoplein at the mother centriole and induced and is considered to function as a chemo- and/or a unscheduled primary cilia formation, which was mechano-sensor. Dysfunction of a primary cilium is reversed by forced trichoplein expression or associated with a broad spectrum of diseases such co-knockdown of KCTD17 (an E3 ligase as polydactyly, obesity and polycystic kidney component protein for trichoplein). Serum disease. In addition, loss of cilia is associated with starvation induced transient Ndel1 degradation, various types of cancer. subsequent to the disappearance of trichoplein at We previously showed that primary cilia the mother centriole. Forced expression of Ndel1 38 suppressed trichoplein degradation and axonemal serum starvation-induced ciliogenesis. Using microtubule extension during ciliogenesis, similar protein array and siRNA screens, we identified to trichoplein induction or KCTD17 knockdown. KCTD17 as a substrate adaptor for Cul3-RING E3 Most importantly, the proportion of ciliated and ligase (CRL3) that polyubiquitylates trichoplein. quiescent cells was increased in kidney tubular SiRNA-mediated KCTD17 depletion prevented epithelia of newborn Ndel1-hypomorphic mice. In trichoplein degradation and inactivation of addition, we found obesity in Ndel1-hypomorphic Aurora-A, thereby leading to defective ciliogenesis mice, which is frequently observed in cilia-related after serum starvation. These phenotypes were diseases. Thus, Ndel1 acts as a novel upstream rescued by expression of siRNA-resistant regulator of the trichoplein-Aurora-A pathway to Myc-tagged KCTD17 or co-silencing of trichoplein, inhibit primary cilia assembly. These findings pave and recapitulated by expression of non-degradable the way for future studies evaluating the importance trichoplein mutant. Similar to KCTD17 loss, Cul3 of cilia dynamics in carcinogenesis. depletion also blocked ciliogenesis and trichoplein degradation. These results indicate that Departments of *1Genetic Disease Research and CRL3KCTD17 ubiquitin E3 ligase promotes *4Molecular Pathology, Osaka City University Graduate ciliogenesis by destroying trichoplein. School of Medicine Maintenance of normal trichoplein levels is *2 RIKEN Center for Life Science Technologies essential for cell cycle progression through (Ultrastructural Research Team) regulating ciliogenesis, as excessive trichoplein *3Molecular Profiling Research Center for Drug Discovery (molprof), National Institute of Advanced suppresses unscheduled ciliogenesis in Industrial Science and Technology (AIST) non-proliferating cells, whereas its depletion leads *5Division of Carcinogenesis and Cancer Prevention, to unscheduled ciliogenesis in proliferating cells. National Cancer Center Research Institute Our study revealed that UPS controls degradation of trichoplein to promote ciliogenesis. We propose 2. The ubiquitin-proteasome system that UPS deficiency serves as a potential underlying controls primary cilia formation at the initial mechanism of ciliogenesis, and that UPS regulation step of axoneme extension might provide a novel means of ciliopathy Kasahara, K., Aoki H., Kawamoto E., Kawakami Y.*1, treatment. Kiyono T.*2, Kawamura Y.*3, Goshima N.*1, and Inagaki M. *1Molecular Profiling Research Center for Drug Non-motile primary cilia are microtubule-based Discovery, National Institute of Advanced Industrial sensory organelles that regulate a number of Science and Technology signaling pathways during development and tissue *2Division of Carcinogenesis and Cancer Prevention, homeostasis. Defects in primary cilia formation National Cancer Center Research Institute *3 (ciliogenesis) result in numerous diseases and Japan Biological Informatics Consortium (JBiC) disorders commonly known as ciliopathies. Primary cilia are grown from modified centrioles called 3. Cytokinetic failure induces aneuploidy basal bodies in response to cell cycle exit or entry and aging in vimentin into quiescence, and this process is achieved Tanaka, Hir., Goto, H., Inoko, A., Hayashi, Y., Kobori, K., Tanigawa, N., Makihara, H., Izawa, I., and Inagaki, M. through coordinated interactions between positive Intermediate filaments (IFs), together with and negative regulators of ciliogenesis. However, microtubules and actin filaments, form the the regulatory mechanisms of ciliogenesis remain to cytoskeletal framework in the cytoplasm of be determined in detail. eukaryotic cells. Distinct from the other two major The ubiquitin-proteasome system (UPS) cytoskeletal networks, IF component proteins are controls most aspects of cell physiology including divided into six groups and their composition cell cycling and organelle biogenesis. In this study, depends on tissue type and differentiation step. we identified a newly recognized role of the UPS in Vimentin, a type III IF protein conserved in ciliogenesis. Using human RPE1 (telomerase vertebrate evolution, is expressed in all reverse transcriptase-immortalized retinal pigment mesenchymal cells and highly in lens tissue. epithelia) cells, we could show that proteasome There is increasing evidence that IF activity is essential for ciliogenesis and destruction disassembly is regulated by phosphorylation of of trichoplein, a centriolar protein that negatively Ser/Thr residues in the amino-terminal head regulates ciliogenesis through activation of domains of IF proteins. Site- and phosphorylation Aurora-A kinases. Trichoplein is rapidly degraded state-specific antibodies that can recognize a in a polyubiquitylation-dependent fashion during phosphorylated residue and its flanking sequence 39 are powerful tools to demonstrate site IF-bridge formation, binucleation (tetraploidy), and (domain)-specific IF phosphorylation in cells. extra-centrosome formation were observed Using these antibodies, we first showed that mitotic specifically in VIMSA/SA fibroblasts. These IF phosphorylation is regulated by distinct protein cellular structures disappeared with decreased kinases in a spatiotemporally regulated manner. vimentin expression, leading to increased numbers Further detailed studies revealed that several of aneuploid fibroblasts. Subsequently, VIMSA/SA mitotic kinases such as Aurora-B, Cdk1, Plk1, and fibroblasts exhibited a significant elevation of Rho-kinase, participate in mitotic phosphorylation major senescence-related markers. These of type III IF proteins. On transient expression of abnormalities resulted in impaired wound healing, type III IF proteins mutated at these mitotic one premature aging phenotype. phosphorylation sites to Ala in type III IF-deficient T24 cell line, we found that disturbance of mitotic 4. Novel platform for integrating IF phosphorylation induced an abnormal IF centrosomal functions structure (referred to as an IF bridge) connecting Inoko, A., Hayashi, Y., Kiyono, T.*1, Goshima, N.*2, and two daughter cells during the cytokinetic process. Inagaki, M. These findings indicated that mitotic IF Centrosomes are small but exhibit dynamic phosphorylation is essential for efficient separation conformational changes during cell proliferation of IFs into two daughter cells. Cells with an IF and differentiation, featuring self-duplication, bridge appeared to make two distinct decisions spindle pole formation and primary cilia assembly. regarding cell fate. The IF bridge was often torn off Diseases related to centriolar abnormalities have the two daughter cells, likely by been reported, like microcephaly, malformations cell-adhesion-dependent traction force, resulting in and ciliopathies. Also, cancer cells are believed to the completion of cytokinesis. With the other type lack primary cilia. Our past findings are that (1) cells failed in cytokinesis, resulting in formation of forced ciliation results in cell cycle exit even in binucleate (multinucleate) cells. However, the growing media and (2) an endogenous mechanism significance of mitotic IF phosphorylation during for primary cilia kinetics is the switching of organogenesis and tissue homeostasis remains centriolar Aurora-A mitotic kinase activity through largely unknown. trichoplein. These findings gave us the idea that the In a previous study, we generated knock-in mice centrosome might be a novel therapeutic target. In expressing vimentin that harbors mutations in fact, Aurora-A knockdown is effective for cultured mitotic phosphorylation sites. Homozygotic mice cancer cell-specific mitotic defects due to the lack (VIMSA/SA) presented with microophthalmia and of the ability to form primary cilia. lens cataracts, whereas heterozygotic mice Our subsequent screening of novel targets that (VIMWT/SA) were indistinguishable from the wild regulate centriolar dynamics is ongoing. Regarding type (VIMWT/WT) . In VIMSA/SA mice, lens our previous finding of a protein with similarity to epithelial cells were reduced in number and trichoplein, we have now established its localization exhibited chromosomal instability (CIN), featuring on centrosomes and relations to both centriolar binucleation and aneuploidy. Electron microscopic duplication and spindle pole separation. With its analyses revealed that lens fiber cells of VIMSA/SA antibodies and exogenous expression, precise mice exhibited membrane disorganization similar to centriolar localization at proximal edges and on defects in age-related cataracts. Since the mRNA mother centriole-specific distal appendages, level of the senescence (aging)-related gene was responsible for integrating centrosomal function, significantly elevated in the lens of VIMSA/SA, the proved possible. Its knockdown cells failed to lens phenotypes in VIMSA/SA suggested a possible demonstrate any of the following centrosomal causal relationship between CIN and premature functions: ciliation, centriolar duplication and aging. spindle pole separation. Investigations are In our present study, we addressed whether continuing to provide more precise understanding binucleate tetraploidy precedes aneuploidy or of phenomena and the underlying molecular whether these events occur independently by mechanisms. analyzing dorsal skin wound healing in VIMSA/SA mice. In response to skin injury, vimentin *1Division of Carcinogenesis and Cancer Prevention, National Cancer Center Research Institute expression was elevated in wound areas of *2 subcutaneous fibroblasts in a genotype-independent Molecular Profiling Research Center for Drug Discovery, National Institute of Advanced Industrial manner. During the acute phase of wound healing Science and Technology when vimentin expression was relatively high, 40

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

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 expected to increase the risk of introducing cancer and the number of polymorphisms mutations into mtDNA and nuclear genomic DNA. in mitochondrial DNA In accordance, we analyzed the number of Kumimoto, H. polymorphisms in mtDNA as a surrogate marker for Mitochondria are well known as the organelles ROS level, then evaluating the relationship with in eucaryotes responsible for production of energy risk of esophageal cancer. for cells and also they have well-defined roles in We performed sequencing analysis of D-loop apoptosis. Recently, frequent mutations in region in mtDNA using DNA samples from mitochondrial DNA (mtDNA) have been found in esophageal cancer subjects and non-cancer controls various types of cancer, such as breast cancer and collected in the HERPACC study. At first, we stomach cancer. Our previous analysis of used re-sequencing primers sets created by ABI, mutations in the D-loop region of mtDNA in mitoSEQr. We found that the whole D-loop esophageal tumors demonstrated frequent somatic region could be sequenced with 4 of 8 primer sets mutations (in 34 % of cases). We also determined of mitoSEQr. After sequencing the whole D-loop nuclear genomic instability, but did not find any region, we identified polymorphisms by comparing correlation with somatic mtDNA mutations, these sequences with the common mtDNA suggesting that instability of mtDNA in esophageal sequence. cancer might be independent of nuclear genomic So far, we have completed analyses of instability. polymorphisms in 66 subjects with esophageal Energy as ATP is produced in mitochondria with cancer and 67 non-cancer controls (see Table 1). reactive oxygen species (ROS) as by-products. After analyses of polymorphisms in 185 esophageal Polymorphisms in the genes related to proteins of cancer patients and 185 non-cancer controls, we oxidative phosphorylation may thus elevate ROS will evaluate the relationship between esophageal production by leaking electrons. Therefore, the cancer risk and numbers of mitochondrial number of polymorphisms in mtDNA may polymorphisms. influence ROS levels in cells, which would be

Table 1. Summary of analyses of polymorphism in mtDNA

Data are shown as average numbers / subject except 'number of subjects analyzed'.

Librarians ______

From left to right Mr.T.Matsunaga, Ms.T.Yasuda, Ms.M.Sasanuma, Ms.M.Namura

Publications ______Odunsi, K, Olson, SH, Orlow, I, Orsulic, S, Weber, Journals RP, Paul, J, Pearce, CL, Pejovic, T, Pelttari, LM, Permuth-Wey, J, Pike, MC, Poole, EM, Risch, HA, J001. Ali, AM, Schmidt, MK, Bolla, MK, Wang, Rosen, B, Rossing, MA, Rothstein, JH, Rudolph, Q, Gago-Dominguez, M, Castelao, JE, Carracedo, A, Runnebaum, IB, Rzepecka, IK, Salvesen, HB, A, Garzon, VM, Bojesen, SE, Nordestgaard, BG, Schernhammer, E, Schwaab, I, Shu, XO, Shvetsov, Flyger, H, Chang-Claude, J, Vrieling, A, Rudolph, YB, Siddiqui, N, Sieh, W, Song, H, Southey, MC, A, Seibold, P, Nevanlinna, H, Muranen, TA, Spiewankiewicz, B, Sucheston-Campbell, L, Teo, Aaltonen, K, Blomqvist, C, Matsuo, K, Ito, H, SH, Terry, KL, Thompson, PJ, Thomsen, L, Iwata, H, Horio, A, John, EM, Sherman, M, Tangen, IL, Tworoger, SS, van Altena, AM, Lissowska, J, Figueroa, J, Garcia-Closas, M, Vierkant, RA, Vergote, I, Walsh, CS, Anton-Culver, H, Shah, M, Hopper, JL, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Trichopoulou, A, Bueno-de-Mesquita, B, Krogh, Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, V, Weiderpass, E, Andersson, A, Clavel-Chapelon, YL, Yang, H, Zheng, W, Ziogas, A, Kelemen, LE, F, Dossus, L, Fagherazzi, G, Peeters, PH, Olsen, Berchuck, A, Georgia Chenevix-Trench on behalf A, Wishart, GC, Easton, DF, Borgquist, S, of the, Amg, Schildkraut, JM, Ramus, SJ, Goode, Overvad, K, Barricarte, A, Gonzalez, CA, Sanchez, EL, Monteiro, AN, Gayther, SA, Narod, SA, MJ, Amiano, P, Riboli, E, Key, T, Pharoah, PD. Pharoah, PD, Sellers, TA, Phelan, CM. Alcohol consumption and survival after a breast Epithelial-Mesenchymal Transition (EMT) Gene cancer diagnosis: a literature-based meta-analysis Variants and Epithelial Ovarian Cancer (EOC) Risk. and collaborative analysis of data for 29,239 cases. Genet Epidemiol, 2015. (PMID: 26399219) Cancer Epidemiol Biomarkers Prev, 23: 934-945, 2014. (PMID: 24636975) J003. Arita, K., Tsuzuki, S., Ohshima, K., Sugiyama, T., Seto, M.: Synergy of Myc, cell cycle J002. Amankwah, EK, Lin, HY, Tyrer, JP, regulators and the Akt pathway in the development Lawrenson, K, Dennis, J, Chornokur, G, Aben, of aggressive B-cell lymphoma in a mouse model. KK, Anton-Culver, H, Antonenkova, N, Bruinsma, Leukemia, 28: 2270-2272, 2014. (PMID: F, Bandera, EV, Bean, YT, Beckmann, MW, 25034145) Bisogna, M, Bjorge, L, Bogdanova, N, Brinton, LA, Brooks-Wilson, A, Bunker, CH, Butzow, R, J004. Asai, H., Fujiwara, H., Kitazawa, S., Campbell, IG, Carty, K, Chen, Z, Chen, YA, Kobayashi, N., Ochi, T., Miyazaki, Y., Ochi, F., Chang-Claude, J, Cook, LS, Cramer, DW, Akatsuka, Y., Okamoto, S., Mineno, J., Cunningham, JM, Cybulski, C, Kuzushima, K., Ikeda, H., Shiku, H., Yasukawa, Dansonka-Mieszkowska, A, du Bois, A, Despierre, M.: Adoptive transfer of genetically engineered E, Dicks, E, Doherty, JA, Dork, T, Durst, M, WT1-specific cytotoxic T lymphocytes does not Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, induce renal injury. J Hematol. Oncol., 7:3, 2014. Fasching, PA, Fridley, BL, Gao, YT, (PMID: 24393438) Gentry-Maharaj, A, Giles, GG, Glasspool, R, Goodman, MT, Gronwald, J, Harrington, P, J005. Bargagna-Mohan, P., Lei, L., Thompson, Harter, P, Hasmad, HN, Hein, A, Heitz, F, A., Shaw, C., Kasahara, K., Inagaki, M., Mohan, Hildebrandt, MA, Hillemanns, P, Hogdall, CK, R.: Vimentin phosphorylation underlies Hogdall, E, Hosono, S, Iversen, ES, Jakubowska, myofibroblast sensitivity to withaferin A in vitro A, Jensen, A, Ji, BT, Karlan, BY, Jim, H, Kellar, and during corneal fibrosis. PLoS One, 17: M, Kiemeney, LA, Krakstad, C, Kjaer, SK, e0133399, 2015. (PMID: 26186445) Kupryjanczyk, J, Lambrechts, D, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Leminen, A, Lester, J, J006. Brenner, DR, Amos, CI, Brhane, Y, Levine, DA, Liang, D, Lim, BK, Lissowska, J, Lu, Timofeeva, MN, Caporaso, N, Wang, Y, Christiani, K, Lubinski, J, Lundvall, L, Massuger, LF, DC, Bickeboller, H, Yang, P, Albanes, D, Stevens, Matsuo, K, McGuire, V, McLaughlin, JR, VL, Gapstur, S, McKay, J, Boffetta, P, Zaridze, D, McNeish, I, Menon, U, Milne, RL, Modugno, F, Szeszenia-Dabrowska, N, Lissowska, J, Rudnai, P, Moysich, KB, Ness, RB, Nevanlinna, H, Eilber, U, Fabianova, E, Mates, D, Bencko, V, Foretova, L,

Janout, V, Krokan, HE, Skorpen, F, Gabrielsen, production. Carcinogenesis, 35: 164-72, 2014. ME, Vatten, L, Njolstad, I, Chen, C, Goodman, G, (PMID: 23917077) Lathrop, M, Vooder, T, Valk, K, Nelis, M, Metspalu, A, Broderick, P, Eisen, T, Wu, X, J010. Chihara, D, Ito, H, Izutsu, K, Hattori, M, Zhang, D, Chen, W, Spitz, MR, Wei, Y, Su, L, Xie, Nishino, Y, Ioka, A, Matsuda, T, Ito, Y. Advance D, She, J, Matsuo, K, Matsuda, F, Ito, H, Risch, A, and stagnation in the treatment of patients with Heinrich, J, Rosenberger, A, Muley, T, lymphoma and myeloma: Analysis using Dienemann, H, Field, JK, Raji, O, Chen, Y, population-based cancer registry data in Japan from Gosney, J, Liloglou, T, Davies, MP, Marcus, M, 1993 to 2006. Int J Cancer, 137: 1217-1223, 2015. McLaughlin, J, Orlow, I, Han, Y, Li, Y, Zong, X, (PMID: 25694231) Johansson, M, Investigators, E, Liu, G, Tworoger, SS, Le Marchand, L, Henderson, BE, Wilkens, LR, J011. Chihara, D, Ito, H, Katanoda, K, Shibata, Dai, J, Shen, H, Houlston, RS, Landi, MT, A, Matsuda, T, Sobue, T, Matsuo, K. Incidence of Brennan, P, Hung, RJ. Identification of lung myelodysplastic syndrome in Japan. J Epidemiol, cancer histology-specific variants applying 24: 469-473, 2014. (PMID: 25088696) Bayesian framework variant prioritization approaches within the TRICL and ILCCO consortia. J012. Chihara, D, Ito, H, Matsuda, T, Shibata, Carcinogenesis, 36: 1314-1326, 2015. (PMID: A, Katsumi, A, Nakamura, S, Tomotaka, S, 26363033) Morton, LM, Weisenburger, DD, Matsuo, K. Differences in incidence and trends of J007. Cai, Q, Zhang, B, Sung, H, Low, SK, haematological malignancies in Japan and the Kweon, SS, Lu, W, Shi, J, Long, J, Wen, W, Choi, United States. Br J Haematol, 164: 536-545, 2014. JY, Noh, DY, Shen, CY, Matsuo, K, Teo, SH, Kim, (PMID: 24245986) MK, Khoo, US, Iwasaki, M, Hartman, M, Takahashi, A, Ashikawa, K, Matsuda, K, Shin, J013. Chihara, D, Ito, H, Matsuo, K. MH, Park, MH, Zheng, Y, Xiang, YB, Ji, BT, Comparison of the incidence and trends of Park, SK, Wu, PE, Hsiung, CN, Ito, H, Kasuga, Y, hematologic malignancies between Japan and the Kang, P, Mariapun, S, Ahn, SH, Kang, HS, Chan, United States. Rinsho Ketsueki, 56: 366-374, 2015. KY, Man, EP, Iwata, H, Tsugane, S, Miao, H, (PMID: 25971266) Liao, J, Nakamura, Y, Kubo, M, Consortium, DG-O, Delahanty, RJ, Zhang, Y, Li, B, Li, C, Gao, J014. Chihara, D, Izutsu, K, Kondo, E, Sakai, YT, Shu, XO, Kang, D, Zheng, W. Genome-wide R, Mizuta, S, Yokoyama, K, Kaneko, H, Kato, K, association analysis in East Asians identifies breast Hasegawa, Y, Chou, T, Sugahara, H, Henzan, H, cancer susceptibility loci at 1q32.1, 5q14.3 and Sakamaki, H, Suzuki, R, Suzumiya, J. High-dose 15q26.1. Nat Genet, 46: 886-890, 2014. (PMID: chemotherapy with autologous stem cell 25038754) transplantation for elderly patients with relapsed/refractory diffuse large B cell lymphoma: a J008. Camargo, MC, Kim, WH, Chiaravalli, nationwide retrospective study. Biol Blood Marrow AM, Kim, KM, Corvalan, AH, Matsuo, K, Yu, J, Transplant, 20: 684-689, 2014. (PMID: 24492141) Sung, JJ, Herrera-Goepfert, R, Meneses-Gonzalez, F, Kijima, Y, Natsugoe, S, Liao, LM, Lissowska, J, J015. Chihara, D, Kagami, Y, Kato, H, Yoshida, Kim, S, Hu, N, Gonzalez, CA, Yatabe, Y, N, Kiyono, T, Okada, Y, Kinoshita, T, Seto, M. Koriyama, C, Hewitt, SM, Akiba, S, Gulley, ML, IL2/IL-4, OX40L and FDC-like cell line support Taylor, PR, Rabkin, CS. Improved survival of the in vitro tumor cell growth of adult T-cell gastric cancer with tumour Epstein-Barr virus leukemia/lymphoma. Leuk Res, 38: 608-612, 2014. positivity: an international pooled analysis. Gut, 63: (PMID: 24679586) 236-243, 2014. (PMID: 23580779) J016. Chornokur, G, Lin, HY, Tyrer, JP, J009. Chew, SH., Okazaki, Y., Nagai, H., Lawrenson, K, Dennis, J, Amankwah, EK, Qu, X, Misawa, N., Akatsuka, S., Yamashita, K., Jiang, L., Tsai, YY, Jim, HS, Chen, Z, Chen, AY, Yamashita, Y., Noguchi, M., Hosoda, K., Sekido, Permuth-Wey, J, Aben, K, Anton-Culver, H, Y., Takahashi, T., Toyokuni, S.: Cancer-promoting Antonenkova, N, Bruinsma, F, Bandera, EV, role of adipocytes in asbestos-induced mesothelial Bean, YT, Beckmann, MW, Bisogna, M, Bjorge, L, carcinogenesis through dysregulated adipocytokine Bogdanova, N, Brinton, LA, Brooks-Wilson, A,

Bunker, CH, Butzow, R, Campbell, IG, Carty, K, of Hereditary, B, Ovarian, C, Arnold, N, Brauch, Chang-Claude, J, Cook, LS, Cramer, DW, H, Hamann, U, Chang-Claude, J, Khan, S, Cunningham, JM, Cybulski, C, Nevanlinna, H, Ito, H, Matsuo, K, Bogdanova, NV, Dansonka-Mieszkowska, A, du Bois, A, Despierre, Dork, T, Lindblom, A, Margolin, S, kConFab, AI, E, Dicks, E, Doherty, JA, Dork, T, Durst, M, Kosma, VM, Mannermaa, A, Tseng, CC, Wu, AH, Easton, DF, Eccles, DM, Edwards, RP, Ekici, AB, Floris, G, Lambrechts, D, Rudolph, A, Peterlongo, Fasching, PA, Fridley, BL, Gao, YT, P, Radice, P, Couch, FJ, Vachon, C, Giles, GG, Gentry-Maharaj, A, Giles, GG, Glasspool, R, McLean, C, Milne, RL, Dugue, PA, Haiman, CA, Goodman, MT, Gronwald, J, Harrington, P, Maskarinec, G, Woolcott, C, Henderson, BE, Harter, P, Hein, A, Heitz, F, Hildebrandt, MA, Goldberg, MS, Simard, J, Teo, SH, Mariapun, S, Hillemanns, P, Hogdall, CK, Hogdall, E, Hosono, Helland, A, Haakensen, V, Zheng, W, S, Jakubowska, A, Jensen, A, Ji, BT, Karlan, BY, Beeghly-Fadiel, A, Tamimi, R, Jukkola-Vuorinen, Kelemen, LE, Kellar, M, Kiemeney, LA, Krakstad, A, Winqvist, R, Andrulis, IL, Knight, JA, Devilee, C, Kjaer, SK, Kupryjanczyk, J, Lambrechts, D, P, Tollenaar, RA, Figueroa, J, Garcia-Closas, M, Lambrechts, S, Le, ND, Lee, AW, Lele, S, Czene, K, Hooning, MJ, Tilanus-Linthorst, M, Li, Leminen, A, Lester, J, Levine, DA, Liang, D, Lim, J, Gao, YT, Shu, XO, Cox, A, Cross, SS, Luben, R, BK, Lissowska, J, Lu, K, Lubinski, J, Lundvall, L, Khaw, KT, Choi, JY, Kang, D, Hartman, M, Lim, Massuger, LF, Matsuo, K, McGuire, V, WY, Kabisch, M, Torres, D, Jakubowska, A, McLaughlin, JR, McNeish, I, Menon, U, Milne, Lubinski, J, McKay, J, Sangrajrang, S, Toland, RL, Modugno, F, Moysich, KB, Ness, RB, AE, Yannoukakos, D, Shen, CY, Yu, JC, Ziogas, A, Nevanlinna, H, Eilber, U, Odunsi, K, Olson, SH, Schoemaker, MJ, Swerdlow, A, Borresen-Dale, Orlow, I, Orsulic, S, Weber, RP, Paul, J, Pearce, AL, Kristensen, V, French, JD, Edwards, SL, CL, Pejovic, T, Pelttari, LM, Pike, MC, Poole, EM, Dunning, AM, Easton, DF, Hall, P, Risch, HA, Rosen, B, Rossing, MA, Rothstein, JH, Chenevix-Trench, G. Polymorphisms in a Putative Rudolph, A, Runnebaum, IB, Rzepecka, IK, Enhancer at the 10q21.2 Breast Cancer Risk Locus Salvesen, HB, Schernhammer, E, Schwaab, I, Shu, Regulate NRBF2 Expression. Am J Hum Genet, 97: XO, Shvetsov, YB, Siddiqui, N, Sieh, W, Song, H, 22-34, 2015. (PMID: 26073781) Southey, MC, Spiewankiewicz, B, Sucheston, L, Teo, SH, Terry, KL, Thompson, PJ, Thomsen, L, J018. Ebi, H, Oze, I, Nakagawa, T, Ito, H, Tangen, IL, Tworoger, SS, van Altena, AM, Hosono, S, Matsuda, F, Takahashi, M, Takeuchi, Vierkant, RA, Vergote, I, Walsh, CS, S, Sakao, Y, Hida, T, Faber, AC, Tanaka, H, Wang-Gohrke, S, Wentzensen, N, Whittemore, AS, Yatabe, Y, Mitsudomi, T, Yano, S, Matsuo, K. Wicklund, KG, Wilkens, LR, Wu, AH, Wu, X, Woo, Lack of Association between the BIM Deletion YL, Yang, H, Zheng, W, Ziogas, A, Hasmad, HN, Polymorphism and the Risk of Lung Cancer with Berchuck, A, Georgia Chenevix-Trench on behalf and without EGFR Mutations. J Thorac Oncol, 10: of the, Amg, Iversen, ES, Schildkraut, JM, Ramus, 59-66, 2015. (PMID: 25384174) SJ, Goode, EL, Monteiro, AN, Gayther, SA, Narod, SA, Pharoah, PD, Sellers, TA, Phelan, CM. J019. Fernández, E., Lugo, A., Clancy, L., Common Genetic Variation In Cellular Transport Matsuo, K., La, Vecchia, C., Gallus, S.: Smoking Genes and Epithelial Ovarian Cancer (EOC) Risk. dependence in 18 European countries: Hard to PLoS One, 10: e0128106, 2015. (PMID: 26091520) maintain the hardening hypothesis. Prev Med, 81: 314-319, 2015. (PMID: 26441299) J017. Darabi, H, McCue, K, Beesley, J, Michailidou, K, Nord, S, Kar, S, Humphreys, K, J020. Fernandez-Cuesta, L1., Plenker, D., Thompson, D, Ghoussaini, M, Bolla, MK, Dennis, Osada, H., Sun, R., Menon, R., Leenders, F., J, Wang, Q, Canisius, S, Scott, CG, Apicella, C, Ortiz-Cuaran, S., Peifer, M., Bos, M., Daßler, J., Hopper, JL, Southey, MC, Stone, J, Broeks, A, Malchers, F., Schöttle, J., Vogel, W., Dahmen, I., Schmidt, MK, Scott, RJ, Lophatananon, A, Muir, Koker, M., Ullrich, RT., Wright, GM., Russell, PA., K, Beckmann, MW, Ekici, AB, Fasching, PA, Wainer, Z., Solomon, B., Brambilla, E., Heusinger, K, Dos-Santos-Silva, I, Peto, J, Nagy-Mignotte, H., Moro-Sibilot, D., Brambilla, Tomlinson, I, Sawyer, EJ, Burwinkel, B, Marme, CG., Lantuejoul, S., Altmüller, J., Becker, C., F, Guenel, P, Truong, T, Bojesen, SE, Flyger, H, Nürnberg, P., Heuckmann, JM., Stoelben, E., Benitez, J, Gonzalez-Neira, A, Anton-Culver, H, Petersen, I., Clement, JH., Sänger, J., Muscarella, Neuhausen, SL, Arndt, V, Brenner, H, Engel, C, LA., la Torre, A., Fazio, VM., Lahortiga, I., Meindl, A, Schmutzler, RK, German Consortium Perera, T., Ogata, S., Parade, M., Brehmer, D., 46

Vingron, M., Heukamp, LC., Buettner, R., Zander, H, Yokoi, K, Tajima, K, Takezaki, T. Cigarette T., Wolf, J., Perner, S., Ansén, S., Haas, SA., smoke inhalation and risk of lung cancer: a Yatabe, Y., Thomas, RK.: CD74-NRG1 fusions in case-control study in a large Japanese population. lung adenocarcinoma. Cancer Discov, 4: 415-22, Eur J Cancer Prev, 2014. (PMID: 24911999) 2014. (PMID: 24469108) J027. Fukumoto, K, Ito, H, Matsuo, K, Tanaka, J021. Fowke, JH, McLerran, DF, Gupta, PC, H, Yokoi, K, Tajima, K, Takezaki, T. Cigarette He, J, Shu, XO, Ramadas, K, Tsugane, S, Inoue, smoke inhalation and risk of lung cancer: a M, Tamakoshi, A, Koh, WP, Nishino, Y, Tsuji, I, case-control study in a large Japanese population. Ozasa, K, Yuan, JM, Tanaka, H, Ahn, YO, Chen, Eur J Cancer Prev, 24: 195-200, 2015. (PMID: CJ, Sugawara, Y, Yoo, KY, Ahsan, H, Pan, WH, 24911999) Pednekar, M, Gu, D, Xiang, YB, Sauvaget, C, Sawada, N, Wang, R, Kakizaki, M, Tomata, Y, J028. Gao, W., Gu, Y., Li, Z., Cai, H., Peng, Q., Ohishi, W, Butler, LM, Oze, I, Kim, DH, You, SL, Tu, M., Kondo, Y., Shinjo, K., Zhu, Y., Zhang, J., Park, SK, Parvez, F, Chuang, SY, Chen, Y, Lee, Sekido, Y., Han, B., Qian, Z., Miao, Y.: JE, Grant, E, Rolland, B, Thornquist, M, Feng, Z, miR-615-5p is epigenetically inactivated and Zheng, W, Boffetta, P, Sinha, R, Kang, D, Potter, functions as a tumor suppressor in pancreatic ductal JD. Associations of Body Mass Index, Smoking, adenocarcinoma. Oncogene, 34: 1629-40, 2015. and Alcohol Consumption With Prostate Cancer (PMID: 24769899) Mortality in the Asia Cohort Consortium. Am J Epidemiol, 182: 381-389, 2015. (PMID: 26243736) J029. Ghoussaini, M, Edwards, SL, Michailidou, K, Nord, S, Cowper-Sal Lari, R, J022. Fujishita, T., Kajino-Sakamoto, R., Desai, K, Kar, S, Hillman, KM, Kaufmann, S, Kojima, Y., Taketo, M.M., Aoki, M.: Antitumor Glubb, DM, Beesley, J, Dennis, J, Bolla, MK, activity of the MEK inhibitor trametinib on Wang, Q, Dicks, E, Guo, Q, Schmidt, MK, Shah, intestinal polyp formation in ApcΔ716 mice involves M, Luben, R, Brown, J, Czene, K, Darabi, H, stromal COX-2. Cancer Sci, 106: 692-699, 2015. Eriksson, M, Klevebring, D, Bojesen, SE, (PMID: 25855137) Nordestgaard, BG, Nielsen, SF, Flyger, H, Lambrechts, D, Thienpont, B, Neven, P, Wildiers, J023. Fujiwara, H., Ochi, T., Ochi, F., H, Broeks, A, Van't Veer, LJ, Th Rutgers, EJ, Miyazaki, Y., Asai, H., Narita, M., Okamoto, S., Couch, FJ, Olson, JE, Hallberg, E, Vachon, C, Mineno, J., Kuzushima, K., Shiku, H., Yasukawa, Chang-Claude, J, Rudolph, A, Seibold, P, M.: Antileukemia multifunctionality of CD4+ T Flesch-Janys, D, Peto, J, Dos-Santos-Silva, I, cells genetically engineered by HLA class Gibson, L, Nevanlinna, H, Muranen, TA, I-restricted and WT1-specific T-cell receptor gene Aittomaki, K, Blomqvist, C, Hall, P, Li, J, Liu, J, transfer. Leukemia. 2015 Jun 24. doi: Humphreys, K, Kang, D, Choi, JY, Park, SK, Noh, 10.1038/leu.2015.155. (PMID: 26104661) DY, Matsuo, K, Ito, H, Iwata, H, Yatabe, Y, Guenel, P, Truong, T, Menegaux, F, Sanchez, M, J024. Fujiyama, T, Oze, I, Yagi, H, Hashizume, Burwinkel, B, Marme, F, Schneeweiss, A, Sohn, C, H, Matsuo, K, Hino, R, Kamo, R, Imayama, S, Wu, AH, Tseng, CC, Van Den Berg, D, Stram, DO, Hirakawa, S, Ito, T, Takigawa, M, Tokura, Y. Benitez, J, Zamora, MP, Perez, JI, Menendez, P, Induction of cytotoxic T cells as a novel Shu, XO, Lu, W, Gao, YT, Cai, Q, Cox, A, Cross, independent survival factor in malignant melanoma SS, Reed, MW, Andrulis, IL, Knight, JA, Glendon, with percutaneous peptide immunization. J G, Tchatchou, S, Sawyer, EJ, Tomlinson, I, Kerin, Dermatol Sci, 75: 43-48, 2014. (PMID: 24802712) MJ, Miller, N, Haiman, CA, Henderson, BE, Schumacher, F, Le Marchand, L, Lindblom, A, J025. Fukatsu, A., Ishiguro, F., Tanaka, I., Margolin, S, Teo, SH, Yip, CH, Lee, DS, Wong, Kudo, T., Nakagawa, K., Shinjo, K., Kondo, Y., TY, Hooning, MJ, Martens, JW, Collee, JM, van Fujii, M., Hasegawa, Y., Tomizawa, K., Mitsudomi, Deurzen, CH, Hopper, JL, Southey, MC, Tsimiklis, T., Osada, H., Hata, Y., Sekido, Y.: RASSF3 H, Kapuscinski, MK, Shen, CY, Wu, PE, Yu, JC, downregulation increases malignant phenotypes of Chen, ST, Alnaes, GG, Borresen-Dale, AL, Giles, non-small cell lung cancer. Lung Cancer, 83: 23-9, GG, Milne, RL, McLean, C, Muir, K, 2014. (PMID: 24246507) Lophatananon, A, Stewart-Brown, S, Siriwanarangsan, P, Hartman, M, Miao, H, J026. Fukumoto, K, Ito, H, Matsuo, K, Tanaka, Buhari, SA, Teo, YY, Fasching, PA, Haeberle, L, 47

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Gallinger, S, Gao, YT, Gapstur, SM, Weiderpass, E, Weinstein, SJ, Wentzensen, N, Garcia-Closas, M, Garcia-Closas, R, Wheeler, W, White, E, Wiencke, JK, Wolk, A, Gastier-Foster, JM, Gaziano, JM, Gerhard, DS, Wolpin, BM, Wong, MP, Wrensch, M, Wu, C, Wu, Giffen, CA, Giles, GG, Gillanders, EM, T, Wu, X, Wu, YL, Wunder, JS, Xiang, YB, Xu, J, Giovannucci, EL, Goggins, M, Gokgoz, N, Yang, HP, Yang, PC, Yatabe, Y, Ye, Y, Yeboah, Goldstein, AM, Gonzalez, C, Gorlick, R, Greene, ED, Yin, Z, Ying, C, Yu, CJ, Yu, K, Yuan, JM, MH, Gross, M, Grossman, HB, Grubb, R, 3rd, Gu, Zanetti, KA, Zeleniuch-Jacquotte, A, Zheng, W, J, Guan, P, Haiman, CA, Hallmans, G, Zhou, B, Mirabello, L, Savage, SA, Kraft, P, Hankinson, SE, Harris, CC, Hartge, P, Hattinger, Chanock, SJ, Yeager, M, Landi, MT, Shi, J, C, Hayes, RB, He, Q, Helman, L, Henderson, BE, Chatterjee, N, Amundadottir, LT. Imputation and Henriksson, R, Hoffman-Bolton, J, Hohensee, C, subset-based association analysis across different Holly, EA, Hong, YC, Hoover, RN, Hosgood, HD, cancer types identifies multiple independent risk 3rd, Hsiao, CF, Hsing, AW, Hsiung, CA, Hu, N, loci in the TERT-CLPTM1L region on Hu, W, Hu, Z, Huang, MS, Hunter, DJ, Inskip, chromosome 5p15.33. Hum Mol Genet, 23: PD, Ito, H, Jacobs, EJ, Jacobs, KB, Jenab, M, Ji, 6616-6633, 2014. (PMID: 25027329) BT, Johansen, C, Johansson, M, Johnson, A, Kaaks, R, Kamat, AM, Kamineni, A, Karagas, M, J126. Watanabe, M, Ito, H, Hosono, S, Oze, I, Khanna, C, Khaw, KT, Kim, C, Kim, IS, Kim, JH, Ashida, C, Tajima, K, Katoh, H, Matsuo, K, Kim, YH, Kim, YC, Kim, YT, Kang, CH, Jung, YJ, Tanaka, H. Declining trends in prevalence of Kitahara, CM, Klein, AP, Klein, R, Kogevinas, M, Helicobacter pylori infection by birth-year in a Koh, WP, Kohno, T, Kolonel, LN, Kooperberg, C, Japanese population. Cancer Sci, 2015. (PMID: Kratz, CP, Krogh, V, Kunitoh, H, Kurtz, RC, 26395018) Kurucu, N, Lan, Q, Lathrop, M, Lau, CC, Lecanda, F, Lee, KM, Lee, MP, Le Marchand, L, J127. Yamada, E., Demachi-Okamura, A., Lerner, SP, Li, D, Liao, LM, Lim, WY, Lin, D, Lin, Kondo, S., Akatsuka, Y., Suzuki, S., Shibata, K., J, Lindstrom, S, Linet, MS, Lissowska, J, Liu, J, Kikkawa, F., Kuzushima, K.: Identification of a Ljungberg, B, Lloreta, J, Lu, D, Ma, J, Malats, N, naturally processed HLA-Cw7-binding peptide that Mannisto, S, Marina, N, Mastrangelo, G, Matsuo, cross-reacts with HLA-A24-restricted ovarian K, McGlynn, KA, McKean-Cowdin, R, McNeill, cancer-specific CTLs. Tissue Antigens, 86:164-171, LH, McWilliams, RR, Melin, BS, Meltzer, PS, 2015. (PMID: 26216489) Mensah, JE, Miao, X, Michaud, DS, Mondul, AM, Moore, LE, Muir, K, Niwa, S, Olson, SH, Orr, N, J128. Yamaguchi, M, Uemura, H, Arisawa, K, Panico, S, Park, JY, Patel, AV, Patino-Garcia, A, Katsuura-Kamano, S, Hamajima, N, Hishida, A, Pavanello, S, Peeters, PH, Peplonska, B, Peters, U, Suma, S, Oze, I, Nakamura, K, Takashima, N, Petersen, GM, Picci, P, Pike, MC, Porru, S, Suzuki, S, Ibusuki, R, Mikami, H, Ohnaka, K, Prescott, J, Pu, X, Purdue, MP, Qiao, YL, Kuriyama, N, Kubo, M, Tanaka, H, Japan Rajaraman, P, Riboli, E, Risch, HA, Rodabough, Multi-institutional Collaborative Cohort Study, G. RJ, Rothman, N, Ruder, AM, Ryu, JS, Sanson, M, Association between brain-muscle-ARNT-like Schned, A, Schumacher, FR, Schwartz, AG, protein-2 (BMAL2) gene polymorphism and type 2 Schwartz, KL, Schwenn, M, Scotlandi, K, Seow, A, diabetes mellitus in obese Japanese individuals: A Serra, C, Serra, M, Sesso, HD, Severi, G, Shen, H, cross-sectional analysis of the Japan Shen, M, Shete, S, Shiraishi, K, Shu, XO, Siddiq, Multi-institutional Collaborative Cohort Study. A, Sierrasesumaga, L, Sierri, S, Loon Sihoe, AD, Diabetes Res Clin Pract, 2015. (PMID: 26497775) Silverman, DT, Simon, M, Southey, MC, Spector, L, Spitz, M, Stampfer, M, Stattin, P, Stern, MC, J129. Yamashita, R., Sato, M., Kakumu, T., Stevens, VL, Stolzenberg-Solomon, RZ, Stram, Hase, T., Yogo, N., Maruyama, E., Sekido, Y., DO, Strom, SS, Su, WC, Sund, M, Sung, SW, Kondo, M., Hasegawa, Y.: Growth inhibitory Swerdlow, A, Tan, W, Tanaka, H, Tang, W, Tang, effects of miR-221 and miR-222 in non-small cell ZZ, Tardon, A, Tay, E, Taylor, PR, Tettey, Y, lung cancer cells. Cancer Med, 4: 551-64, 2015. Thomas, DM, Tirabosco, R, Tjonneland, A, (PMID: 25641933) Tobias, GS, Toro, JR, Travis, RC, Trichopoulos, D, Troisi, R, Truelove, A, Tsai, YH, Tucker, MA, J130. Yamashita, Y., Ito, Y., Isomura, H., Tumino, R, Van Den Berg, D, Van Den Eeden, SK, Takemura, N., Okamoto, A., Motomura, K., Vermeulen, R, Vineis, P, Visvanathan, K, Vogel, Tsujiuchi, T., Natsume, A, Wakabayashi T, U, Wang, C, Wang, C, Wang, J, Wang, SS, Toyokuni S, Tsurumi T.: Lack of presence of the 62 human cytomegalovirus in human glioblastoma. high-risk Chinese population. Cancer Epidemiol Mod Pathol, 27: 922-929, 2014. (PMID: 24336154) Biomarkers Prev, 2014. (PMID: 25086101)

J131. Ye, B., Dai, Z., Liu, B., Wang, R., Yang, J137. Zheng, W, McLerran, DF, Rolland, BA, X., Huang, G., Wang, S., Xia, P., Kuwahara, K., Fu, Z, Boffetta, P, He, J, Gupta, PC, Ramadas, K, Sakaguchi, N., Fan, Z.: Pcid2 inactivates Tsugane, S, Irie, F, Tamakoshi, A, Gao, YT, Koh, developmental genes in human and mouse WP, Shu, XO, Ozasa, K, Nishino, Y, Tsuji, I, embryonic stem cells to sustain their pluripotency Tanaka, H, Chen, CJ, Yuan, JM, Ahn, YO, Yoo, by modulation of Eid1 stability. Stem Cells, 32: KY, Ahsan, H, Pan, WH, Qiao, YL, Gu, D, 623-635, 2014. (PMID: 24167073) Pednekar, MS, Sauvaget, C, Sawada, N, Sairenchi, T, Yang, G, Wang, R, Xiang, YB, Ohishi, W, J132. Yoshida, N., Karube, K., Utsunomiya, A., Kakizaki, M, Watanabe, T, Oze, I, You, SL, Tsukasaki, K., Imaizumi, Y., Taira, N., Uike, N., Sugawara, Y, Butler, LM, Kim, DH, Park, SK, Umino, A., Arita, K., Suguro, M., Tsuzuki, S., Parvez, F, Chuang, SY, Fan, JH, Shen, CY, Chen, Kinoshita, T., Ohshima, K., Seto, M.: Molecular Y, Grant, EJ, Lee, JE, Sinha, R, Matsuo, K, characterization of chronic-type adult T-cell Thornquist, M, Inoue, M, Feng, Z, Kang, D, leukemia/lymphoma. Cancer Res, 74: 6129-6138, Potter, JD. Burden of total and cause-specific 2014. (PMID: 25320005) mortality related to tobacco smoking among adults aged ≥ 45 years in Asia: a pooled analysis of 21 , J133. Yoshida, N., Tsuzuki, S., Karube, K., cohorts. PLoS Med 11: e1001631, 2014. (PMID: Takahara, T., Suguro, M., Miyoshi, H., Nishikori, 24756146) 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 63

Oncogenesis, Springer International Publishing, Reviews and Books 155-182, 2014.

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

Registries in Ottawa, Ottawa, 2014. Abstracts for international conferences

A009. Kanda, T.: Roles of BART microRNAs in A001. Arita, K., Tsuzuki, S., Ohshima, K., EBV-infected epithelial cells. EBV 50th Sugiyama, T., Seto, M.: Synergy of Myc, cell cycle anniversary, Oxford, 2014. regulators and the Akt pathway in a mouse model of B-cell lymphoma. American Society of A010. Kanda, T.: Regulation of cellular gene Hematology Meeting on Lymphoma Biology, expression by EBV-encoded miRNAs in epithelial Colorado Springs, 2014. cells. 39th Annual International Herpesvirus Workshop, Kobe, 2014.

A002. Hosono, S. Polymorphisms in DNA repair genes are associated with endometrial cancer risk among Japanese women. The 19th Japan-Korea A011. Kasugai, Y., Tsuzuki, S., Yoshida, N., Cancer Research Workshop, Jeju Island, 2014. Suguro, M., Takahara, T., Karube, K., Ohshima, K., Seto, M.: HBZ, BCL-xL, Akt, and loss of Ink4a/Arf synergistically transform primary murine A003. Inaba, H., Goto, H., Kasahara, K., T cells and elicit adult T-cell leukemia/lymphoma Kumamoto, K., Yonemura, S., Inoko, A., Yamano, (ATL)-like disease in mice. 13th International S., Wanibuchi, H., He, D., Goshima, N., Kiyono, Conference of Malignant Lymphoma, Lugano, T., Hirotsune, S., Inagaki, M.: Ndel1 suppresses 2015. unscheduled cilia formation in proliferating cells by regulating trichoplein-Aurora-A pathway. The 55th Annual Meeting of the American Society for Cell A012. Kuwahara, K.: The role of mammalian Biology, San Diego, 2015. TREX2 complex in sporadic breast cancers. The 3rd Bandung International Biomolecular

Medicine Conference (BIBMC), Bandung, A004. Inagaki M.: New insights into roles of Indonesia, 2014. intermediate filament (IF) phosphorylation and progeria pathogenesis. The 13th biennial Gordon Conference on Intermediate Filaments, West Dover, A013. Miyama, T., Kawase, T., Kitaura, K., 2014. Chishaki R., Shibata M., Oshima, K., Hamana H., Kishi, H., Kuzushima, K., Saji, H., Suzuki, R.,

Ichinohe, T.: Comprehensive T-Cell Receptor A005. Inagaki, M.: Cancer research on the two Repertoire Analysis Using Deep Sequencing and noteworthy issues: tetraploidy and primary cilia. Single Cell Cloning Reveals Extreme Aichi Cancer Center 50th anniversary International Oligoclonality of Ex Vivo Expanded Symposium, Nagoya, 2015. Cytomegalovirus-Reactive Cytotoxic T-Cells. 57th

Annual Meeting and Exposition, American Society A006. Ito, H. The risk prediction for esophaneal of Hematology, Orlando, 2015. cancer by drinking, smoking, and the polymorphisms of ALDH2 and ADH1B. AACR A014. Mohan, R., Lei, L., Thompson, A., ANNUAL MEETING 2015, Philadelphia, 2015. Shaw, C., Kasahara, K., Inagaki, M., Bargagna-Mohan, P.: Vimentin Phosphorylation

Patterns Differentiate Corneal Fibroblasts from A007. Ito, H., Oze, I., Hosono, S., Watanabe M., Myofibroblasts In Vitro and During Fibrosis. Tanaka, H., Matsuo, K. Cumulative risks of gastric Association in Research in Vision and cancer by PSCA polymorphism, Helicobacter Ophthalmology (ARVO) meeting 2015, Colorado, Pylori infection and smoking history in Japan. 2015. American Association for Cancer Research

, ANNUAL MEETING 2014, SAN DIEGO 2014. A015. Murakami-Tonami, Y., Kishida, S., Takeuchi, I., Katou, Y., Maris, J M., Ichikawa, H., Kondo, Y., Sekido, Y., Shirahige, K.,

A008. Ito, H., Tanaka, H. Descriptive Murakami, H., Kadomatsu, K.: Inactivation of epidemiology of cancer in the Japanese "oldest-old" SMC2 shows a Synergistic Lethal Response in population. International Association of Cancer MYCN-amplified Neuroblastoma Cells. Advances 65

In Neuroblastoma Research, Cologne, 2014. A024. Suguro, M., Takahara, T., Arita, K., Yoshida, N., Kakiuchi, T., Kasugai, Y., Toby,

Dylan, Hocking., Takeuchi, I., Tsuzuki, S., Seto, A016. Nakagawa, H., Tamura, T., Mitsuda, Y., M.: Common Progenitor Cells Give Rise to Diffuse Goto, Y., Kamiya, Y., Kondo, T., Tanaka, H., Large B-Cell Lymphoma at Diagnosis and Relapse. Wakai, K., Hamajima, N. The association between American Society of Hematology Meeting on serum ferritin levels and atrophic gastritis among Lymphoma Biology, Colorado Springs, 2014. Japanese adults. International Association of

Cancer Registries in Ottawa, Ottawa, 2014,. A025. Tanaka, H. Advance in the Japanese

Multi-Institutional Collaborative Study. 7th General A017. Narita, Y., Murata, T., Kanda, T., Assembly and International Conference of Asian Kimura, H., Tsurumi, T.: A conserved motif in the Pacific Organization for Cancer Prevention (2014 Pre-N-terminal domain of Epstein-Barr virus DNA APOCP), Taipei, 2014. polymerase catalytic subunit is required for the de novo EBV genome synthesis. 39th Annual A026. Tanaka H., Goto H., Inoko A., Makihara International Herpesvirus Workshop, Kobe, 2014. H., Izawa I., and Inagaki M.: Phosphorylation-deficient vimentin mutant mice A018. Narita, Y., Murata, T., Kimura, H., develop premature aging via aneuploidy and Tsurumi, T.: A conserved motif in the cellular senescence. The 13th biennial Gordon Pre-N-terminal domain of Epstein-Barr virus DNA Conference on Intermediate Filaments, West Dover, polymerase catalytic subunit is required for the de 2014. novo EBV genome synthesis. EBV 50th anniversary, Oxford, 2014. A027. Tawara, I., Masuya, M., Kageyama, S., Nishida, T., Terakura, S., Murata, M., Fujiwara, A019. Oneyama, C.: MicroRNAs as the H., Akatsuka, Y., Ikeda, H., Miyahara, Y., Tomura, fine-tuners of Src oncogenic signaling. D., Nukaya, I., Takesako, K., Emi, N., Yasukawa, JARI&JSEV 7th Annual Meeting, Hiroshima, M., Katayama, N., Shiku, H.: Adoptive 2015. Transfer of WT1-Specific TCR Gene-Transduced Lymphocytes in Patients with Myelodysplastic A020. Sakura, T., Hayakawa, F., Sugiura, I., Syndrome and Acute Myeloid Leukemia. Blood. Imai, K., Usui, N., Fujisawa, S., Murayama, T., 126:97, 2015. 57th American Society of Yujiri, T., Kiyoi, H., Ohnishi, K., Miyazaki, Y., Hematology Annual Meeting, Orland, FL, Dec. 5, Ohtake, S., Kobayashi, Y., Matsuo, K.: 2015. Effectiveness of High-Dose MTX Therapy for Adult Ph-Negative ALL By Randomized Trial: A028. Urayama, Y. K., Takagi, M., Kawaguchi, JALSG ALL202-O. 57th American Society of T., Matsuo, K., Tanaka, Y., Arakawa, Y., Hematology Annual Meeting, Orlando, 2015. Hasegawa, D., Yuza, Y., Kaneko, T., Noguchi, Y., Taneyama, Y., Ota, S., Inukai, T., Yanagimachi, A021. Sekido, Y.: Hippo pathway inactivation in M., Keino, D., Koike, K., Toyama, D., Nakazawa, malignant mesothelioma cells. International Y., Kurosawa, H., Nakamura, K., Moriwaki, K., Mesothelioma Interest Group, Cape Town, 2014. Goto, H., Sekinaka, Y., Morita, D., Kato, M., Koh, K., Ishida, Y., Ohara, A., Mizutani, S., Matsuda, A022. Sekido, Y.: Hippo pathway inactivation in F., Manabe, A.: Genetic Susceptibility Loci for malignant mesothelioma cells. Keystone Childhood Acute Lymphoblastic Leukemia Among Symposium The Hippo Pathway: Signaling, Japanese. 57th American Society of Hematology Development and Disease, New Mexico, 2015. Annual Meeting and Exposition, Orlando, 2015.

A023. Sekido, Y.: Hippo pathway dysregulation A029. Yoshida, N., Karube, K., Utsunomiya, A., in mesothelioma cells. 16th World Conference on Tsukasaki, K., Imaizumi, Y., Taira, N., Uike, N., Lung Cancer, Denver, 2015. Nakamura, S., Umino, A., Suguro, M., Tsuzuki, S., Ohshima, K., Seto. M.,: Molecular Characterization

66 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.

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.

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 -

______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)

Abstracts

Targeting KRAS-induced stemness understanding of interactions between mutation Frank McCormick and Man-Tzu Wang status, the prognosis of ER+ breast cancer, and the University of California, San Francisco - Helen Diller effectiveness of endocrine therapy; 3) an inadequate Family Comprehensive Cancer Center, USA collection of patient-derived xenograft (PDX) Of the three Ras genes, KRAS, NRAS and models for luminal breast cancer that fully HRAS, KRAS is by far the major contributor to encompass the heterogeneity of the disease; 4) the human cancer, whereas HRAS is rarely activated. logistical barriers of developing adjuvant strategies In spite of this dramatic difference, KRAS and to exploit rare drivers present in less than 5% of HRAS interact with the same effectors and are tumor samples; 5) insufficient genomic discovery equally potent at transforming cells in culture. efforts directed towards samples accrued from However, cells transformed by KRAS have unique patients suffering from endocrine therapy resistant properties relative to HRAS: they cause a stem-like disease progression and 6) an incomplete phenotype that enables them to grow as spheres in understanding of how complex somatic genotypes culture, to establish tumors in mice at high drive the biochemical events responsible for the efficiency and to resist the effects of multiple “hallmarks” of luminal cancer. chemotherapy and targeted drugs. These effects are To better address these issues, five areas of due to KRAS’ ability to bind calmodulin, and to investigation will be discussed: 1) somatic mutation inhibit calmodulin-dependent kinase. Low CaM diagnosis in DNA from primary breast cancer kinase promotes wnt signaling and initiates a set of samples from patients treated with adjuvant programs that confer stemness. Binding of K-Ras to tamoxifen and followed for over 20 years; 2) DNA calmodulin is prevented by phosphorylation of and RNA sequencing of samples accrued from K-Ras on serine-181, by protein kinase C. patients treated with neoadjuvant endocrine therapy Treatment of mice with a natural product, prostratin, to define the molecular origins of intrinsic that activates PKC and K-Ras phosphorylation aromatase inhibitor resistance and to identify prevents initiation of pancreatic tumors in xenograft pharmacological hypothesis; 3) efforts to expand models. Part of the “stemness” program initiated by and catalog patient-derived xenografts from ER+ K-Ras involves secretion of the cytokine LIF, an breast cancers, including the use of mass IL-6 family member with a unique role in spectrometry-based analysis of their proteomes and maintaining stemness. Neutralization of LIF with a phosphoproteomes to expand our knowledge of the monoclonal antibody reduces stemness and biochemistry of individual tumors; 4) a functional sensitizes established pancreas tumors to and pharmacological investigation of mutations in gemcitabine. We propose that attacking targets in ESR1, including resistance-activating chromosomal these stem-like pathways offers new opportunities translocations, and 5) the development of a for therapeutic intervention in KRAS-driven neoadjuvant endocrine therapy strategy that cancers. identifies patients with intrinsic endocrine therapy resistance within a month of starting treatment so Genome-directed therapeutics for that they can be triaged to mutation-matched endocrine therapy resistant ER+ breast investigational treatment. cancer Matthew J. Ellis Trans-ethnic landscape of hepatocellular Lester and Sue Smith Breast Center, Baylor College of carcinoma genomics Medicine, USA Tatsuhiro Shibata1,2, David A. Wheeler3, and Hiroyuki As a result of improvements in DNA and RNA Aburatani4 sequencing techniques the genomic structure of 1Division of Cancer Genomics, National Cancer Center; estrogen receptor positive breast cancer is 2Laboratory of Molecular Medicine, The Institute of increasingly well documented, but extracting Medical Science; 3Human Genome Sequencing Center, clinically actionable information from these Baylor College of Medicine, USA; 4Genome Science complex data sets has proved fraught with Division, Research Center for Advanced Science and difficulties. Barriers to progress include the lack of Technology, The University of Tokyo pharmacological hypotheses for novel luminal Multiple etiological factors (hepatitis virus breast cancer tumor suppressor genes (e.g. infection, alcohol, obesity etc) are associated with MAP3K1, MLL3, SF3B1); 2) a lack of a full the occurrence of hepatocellular carcinoma (HCC) and their contributions diverse among ethnicity. To

71 elucidate genetic diversities in HCC genomes with 1) target gene alterations (T790M mutation in regards to ethnic and epidemiological differences, EGFR-TKI or L1196M and other mutations in ALK, we have conducted the trans-ethnic cancer genome 2) activation of additional kinases (e.g., MET, research under the umbrella of the International HER2 for EGFR, and KIT, EGFR, SRC for ALK) Cancer Genome Consortium (ICGC) and The bypassing the inhibition of the original kinases, and Cancer Genome Atlas (TCGA). 3) other mechanisms including We performed whole exome sequencing of 514 epithelial-mesenchymal transition, small cell lung pairs of HCC, which include different ethnic cancer transformation, etc. populations (424 cases from the Japanese cohort To overcome T790M gatekeeper mutations, and 90 from the US cohort) with various etiological so-called third generation EGFR inhibitors that backgrounds. Furthermore, whole exome data of selectively inhibit EGFR-T790M while sparing the 105 HCC cases from TCGA was included in the wild-type EGFR are being actively developed. mutation signature analysis. Mutation call Likewise, ALK-TKIs of a newer generation are algorithms of three collaborating genome centers active at least for some of the secondary mutations (National Cancer Center, Tokyo, Research Center found in crizotinib-resistant tumors. Tumor for Advanced Science and Technology in the resistance caused by the bypass track can be coped University of Tokyo, and Baylor College of with by combination of the inhibitors for the Medicine, Houston) were adjusted and validated by original kinase and the bypassing kinases. the Ion Proton sequencer. In total, more than However, even with these strategies, cancer 100,000 somatic mutations were collected, and their cells are smart enough to escape from the therapy signatures were significantly associated with using other mechanisms. Heterogeneities in terms ethnicity and gender, but not with the hepatitis virus of resistant mechanisms within a single patient status. In addition to TP53, WNT, and SWI/SNF become evident when specific therapeutic pressure pathways, aberrant activation of the TERT pathway persists. Therefore, we also need to have by various mechanisms (promoter/coding mutations, armamentarium that utilizes other mechanisms to gene amplification and viral genome integration) cure lung cancer. Recent advances of was found to play a central role in immunotherapy targeting PD-1/PD-L1 appear hepatocarcinogenesis. Aggregation of the large attractive in this respect. These mechanism-driven cancer genome data by ICGC and TCGA has therapeutic approaches will convert this fatal rapidly progressed. In addition to the cross-tumor disease into a more chronic disorder, and eventually analysis (Pan-Cancer study), population-based into a curable disease with the least patient burdens. meta-cancer genome analysis would provide us unique and diverse landscapes of the cancer Lgr5+ stem cells in epithelial self-renewal genomes on this planet. and cancer of the stomach and ovary Nick Barker, Marc Leushacke, Annie Ng Acquired resistance in targeted therapy A-STAR* Institute of Medical Biology, Singapore against driver gene mutation in lung cancer The availability of robust cell-surface markers for Tetsuya Mitsudomi1, Kenichi Suda1, Hiroshi Mizuuchi1, identifying and isolating adult stem cells is essential Yoshihisa Kobayashi1, Kazuto Nishio2, and Yasushi for studying both their normal in-vivo function Yatabe3 during tissue renewal and for evaluating their Department of Thoracic Surgery1 and Genome Biology2, contribution to cancer. Lgr5, a Wnt target gene 3 Kinki Unversity Faculty of Medicine; Department of expressing a 7-TM receptor that functions as Pathology and Moleclular Diagnostics, Aichi Cancer facultative component of the Wnt receptor complex, Center Hospital has been shown to selectively mark stem cells in a Discovery of activating mutation of the EGFR range of rapidly renewing tissues, including the gene in adenocarcinoma of the lung in 2004 opened small intestine, colon, stomach, hair follicle and the era of personalized therapy in thoracic oncology. developing kidney. Clonal fate mapping employing These tumors are highly dependent on the EGFR the stem cell-specific Lgr5-CreERT2 line has been pathway and EGFR-tyrosine kinase inhibitors (TKI) used to further dissect how these adult stem cell significantly prolong progression free survival in pools maintain tissue homeostasis and contribute to these patients compared with chemotherapy. In tissue repair following damage. Additionally, 2007, EML4-ALK translocation was found and targeted in-vivo mutation of the Lgr5+ve adult stem these tumors are very sensitive to ALK-TKI. cell pools using the same Lgr5-CreERT2 model has However, acquired resistance inevitably develops been used to determine the contribution of stem usually after a median of 10 months. The cells to tumor initiation and progression in various mechanisms for this resistance can be classified into

72 epithelia. A summary of the latest findings in the vimentin with mitotic phosphorylation-defective stomach and ovary will be presented here. mutations to impair cytokinesis. Homozygotic (VIMSA/SA) mice presented with microophthalmia Regulation of cell differentiation by actin and cataracts, in which lens epithelial cells dynamics and its application in cancer exhibited binucleation and aneuploidy, along with treatment premature aging. We further analyzed the ability to Hideyuki Saya and Hiroyuki Nobuse repair wounds in the skin of VIMSA/SA mice, and Division of Gene Regulation, Institute for Advanced found that some subcutaneous tetraploid fibroblasts Medical Research, School of Medicine, Keio University caused by cytokinetic failure enter a new cell cycle Differentiation status is strongly associated with the and then develop into aneuploid fibroblasts in vivo, behavior of cancer cells. Therefore, changes in the which promotes premature aging. We suggest that cellular context, which regulates the differentiation tetraploidy without the genetic alteration of potential, may serve in novel therapeutic strategies cancer-related genes may be associated with in treating cancers. premature aging rather than carcinogenesis. We have established a mouse osteosarcoma (OS) Non-motile primary cilia are microtubule-based model through overexpression of c-MYC in bone sensory organelles that regulate a number of marrow stromal cells (BMSCs) derived from signaling pathways during development and tissue Ink4a/Arf (-/-) mice. In this model, we found that homeostasis. Tumor cells are known to often lack the loss of adipogenic potential was an essential primary cilia, but whether their loss is directly event for OS development. Therefore, our linked to tumorigenesis is completely unclear. We understanding of regulatory mechanisms of have recently found that ubiquitin-proteasome adipocyte differentiation would greatly contribute machinery removes trichoplein, a negative regulator to control OS tumorigenesis. of ciliogenesis, from mother centrioles and thereby Adipocytic differentiation is accompanied by the causes Aurora-A inactivation, leading to adoption of a rounded cell shape that is ciliogenesis. We have identified KCTD17 as a characteristic of mature adipocytes. Cell shape is substrate-adaptor for Cul3-RING E3 ligases determined primarily by the actin cytoskeleton. We (CRL3s) that polyubiquitylates trichoplein. have recently found a novel regulatory mechanism Depletion of KCTD17 specifically arrests of adipocyte differentiation, in which regulation of ciliogenesis at the initial step of axoneme (ciliary transcriptional coactivator MKL1 by actin microtubule doublet) extension through aberrant cytoskelton dynamics drives adipocyte trichoplein-Aurora-A activity. We would like to differentiation mediated by PPARγ, a master discuss the relationship between primary cilia and transcriptional regulator of adipogenesis. cancer stem cells, which may be implicated in drug Accordingly, adipocyte differentiation can be resistance against cancer chemotherapy. induced by the disruption of actin stress fibers through down-regulation of RhoA-ROCK signaling. T-cell therapy for cancer using gene Based on this concept, we attempted to induce modified T cells and strategies to overcome adipocyte differentiation in OS cells, which resulted tumor escape or immunosuppression in a significant suppression of tumorigenesis. Gianpietro Dotti Induction of trans-differentiation in cancer stem Center for Cell and Gene Therapy, Baylor Colledge of cells by regulating actin cytoskeleton dynamics is a Medicine, USA potential approach for some tumor types. T-lymphocyte-based treatments have enormous potential in cancer patients. Over the past decade, T Cancer research on the two noteworthy cells mo dified to express chimeric antigen issues: tetraploidy and primary cilia receptors (CARs) have had clinical success in Masaki Inagaki B-lymphocyte derived malignancies. In the specific Division of Biochemistry, Aichi Cancer Center Research context of CAR-T cells therapies for B-cell Institute and Department of Cellular Oncology, Nagoya malignancies we developed at Baylor a strategy University Graduate School of Medicine aimed at achieving antitumor effects, but limiting Tetraploidy, a state in which cells have doubled the prolonged B-cell aplasia caused the infusion of chromosomal sets, is observed in ~20% solid CD19-CAR-specific T cells. We are currently tumors and considered to frequently precede targeting the k-light chain of human aneuploidy in carcinogenesis. Tetraploidy is also immunoglobulins expressed on the cell surface of detected during tissue differentiation and aging k+lymphoma cells in an effort to target lymphomas process. We generated knock-in mice featuring cells but spare normal l+B-lymphocytes. An update

73 of the clinical trial currently ongoing will be image guidance. presented. There are two routes to access to the target In contrast to B-cell malignancies, the clinical lesion; trans-canal and direct puncture. The typical efficacy of CAR-T cells remains limited in solid type of trans-canal approach is transarterial tumors. This unfavorable outcome could be due to chemoembolization (TACE) for hepatocellular the insufficient migration of the infused T cells to carcinoma (HCC), in which the feeding arteries are the tumor site and to the immunosuppressive occluded with anticancer drug to kill tumor cells characteristics of the tumor environment, which with stasis of blood flow. TACE could obtain total inhibit the effector function and proliferation of necrosis if the HCC tumor is hyper-vascular and those few T cells that do reach the tumor. We less than 5cm in diameter. In a decade, recently found that tumor-specific engineered T microspheres with drug eluting and Yttrium-90 lymphocytes expanded ex vivo for adoptive T-cell have been developed to treat HCCs with various therapy are defective in their capacity to degrade stages. The other approach with percutaneous direct one critical component of the extracellular matrix. puncture is thermal ablation, such as radiofrequency We also found that this defect can be however ablation (RFA), microwave ablation, cryoablation repaired by the ectopic expression of the enzyme for tumors in the liver, kidney, lung, etc. TACE and heparanase. We also found that armed oncolytic RFA are established as the standard treatment for viruses expressing RANTES and IL-15 can be used early and intermediate stage HCC. to favor the migration of CAR-T cells at the tumor Moreover, there are novel IR treatments; site and promote the survival of CAR-T cells within high-intensity focused ultrasounds (HIFU) and the hostile tumor environment. irreversible electroporation (IRE). HIFU kills tumor cells with thermal ablation by high-intensity Loss of autophagy causes metabolic focused ultrasounds without needle puncture. IRE changes through a transcription-factor kills tumor cells with membrane with pathway electroporation by high voltage pulse without the Masaaki Komatsu destruction of anatomical structures. Department of Biochemistry, School of Medicine, Niigata IR can be complementary with other treatment University modalities because the mechanism of anti-tumor Autophagy provides starved cells with amino effect in IR is completely different from that of acids, free fatty acids, and glucose for new protein medical and radiation therapy. synthesis energy production; autophagy also On the other hand, IR is difficult to establish controls the quality and quantity of organelles such evidence by clinical trials, because the clinical as mitochondria. Therefore, it is plausible that results in IR greatly depend on the operator’s skills autophagy might be integrated with metabolic and equipment. We started to conduct many pathways. Indeed, suppression of autophagy causes multi-institutional clinical trials in Japan more myopathy, tumorigenesis, and metabolic disorders earlier than western countries, however, still it is in mice and humans. However, the metabolic very challenging for us to establish IR as one of the changes associated with deficiencies in autophagy standard treatments in the oncology field. are largely unknown. Furthermore, it remains unclear whether the major predisposing factor for Apoptosis and exposure of the aforementioned diseases in the absence of phosphatidylserine normal autophagic activity is a simple deficit in Shigekazu Nagata supply of molecular building blocks, dysregulation Department of Medical Chemistry, Graduate School of of mitochondrial homeostasis, or some other cause. Medicine, Kyoto University Here, we show that deficiencies in autophagy are Apoptotic cells are swiftly engulfed by associated with rearrangement of glucose and macrophages. If this process does not occur glutamine metabolism via a transcriptional properly, materials released from dead cells activate regulatory mechanism. the immune system, leading to systemic lupus erythematosus-type autoimmune disease. Interventional radiology in oncology Phospholipids in plasma membranes are Yasuaki Arai asymmetrically distributed between inner and outer National Cancer Center Hospital leaflets, and phosphatidylserine (PtdSer) is IR is a minimally invasive treatment modality in exclusively localized in the inner leaflet. The which small devices are percutaneously inserted asymmetrical distribution of phospholipids is into a patient’s body with minimum incision under maintained by an ATP-dependent phospholipid

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 translocase or flippase. When cells undergo inactivated by caspase-mediated cleavage, apoptosis, or platelets are activated, the indicating that in addition to the caspase-mediated asymmetrical distribution of phospholipids is activation of scramblase, inactivation of flippase is disrupted by scramblase, leading to required to expose PtdSer during apoptosis. PtdSer-exposure. The PtdSer exposed on dead cell Lymphoma cells that lack the flippase surface is recognized by macrophages as an “eat constitutively expose PtdSer, are engulfed by me” signal, while PtdSer on activated platelets macrophages, and can not develop tumors in nude provides the scaffold for clotting factors. We mice. These results indicate that PtdSer is necessary recently identified two membrane proteins and sufficient as an “eat me” signal to be (TMEM16F and Xkr8) as phospholipid scramblases, recognized by macrophages, and the and a pair of membrane proteins (ATP11C and PtdSer-expressing tumor cells can be killed by CDC50A) as a flippase. TMEM16F, a protein with being engulfed by macrophages.