iPS-derived differentiation-related tumor models and multi-omics analysis

• Project/Area Number: 17K19623
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Tumor biology and related fields
• Research Institution: Research Institute for Clinical Oncology, Saitama Cancer Center
• Principal Investigator: Kamijo Takehiko 埼玉県立がんセンター(臨床腫瘍研究所), 臨床腫瘍研究所, 所長 (90262708)
• Co-Investigator(Kenkyū-buntansha): 大平 美紀 埼玉県立がんセンター(臨床腫瘍研究所), 臨床腫瘍研究所, 研究員 (20311384) ; 杉野 隆一 埼玉県立がんセンター(臨床腫瘍研究所), 臨床腫瘍研究所, 研究員 (90749516)
• Research Collaborator: Mukai Kyousuke ; Takenobu Hisanori ; Yamada Yasuhiro ; Jesmin Akter
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: iPS / 小児がん / 神経芽腫 / オミックス解析 / エピゲノム / 発がんモデル / 発生・分化 / 癌

Outline of Final Research Achievements

We established 3 wild-type and 1 Li-Fraumeni syndrome patient-derived neural crest cells (NCC) from iPS cells and confirmed the differentiation by FACS analysis using NCC marker p75 antibody, suggesting > 90 % differentiation. We performed multi-omics analysis including transcriptome, DNA methylome, and ChIP sequence of histone codes to study the differentiation mechanism related to tumorigenesis. Transformation of the NCCs were successfully performed by MYCN oncogene expression and soft agar colony formation experiments. Tumor formation in immune-deficient mice was studied and omics analysis is ongoing.

Academic Significance and Societal Importance of the Research Achievements

MYCN遺伝子を時間的（iPSからの分化誘導のタイムコース）・空間的（iPSからの神経堤細胞および交感神経細胞への分化誘導）に誘導する系は、神経芽腫発がん機構の解析に大きな進歩をもたらし、かつ新たな治療標的検出につながる研究と考えられる。更に、MYCN遺伝子発現異常による難治性がん（神経芽腫、脳腫瘍、小児腫瘍）の治療法を開発するためにも有用であり、従来の腫瘍細胞での遺伝子発現やトランスジェニックマウスでは不可能であった遺伝子発現誘導システムを構築して解析する研究である。

Research Products

• [Journal Article] Combined Genetic and Chromosomal Characterization of Wilms Tumors Identifies Chromosome 12 Gain as a Potential New Marker Predicting a Favorable Outcome (2019)
  • Author(s): Haruta Masayuki、Arai Yasuhito、Okita Hajime、Tanaka Yukichi、Takimoto Tetsuya、Sugino Ryuichi P.、Yamada Yasuhiro、Kamijo Takehiko、Oue Takaharu、Fukuzawa Masahiro、Koshinaga Tsugumichi、Kaneko Yasuhiko
  • Journal Title: Neoplasia Volume: 21 Issue: 1 Pages: 117-131
  • DOI: 10.1016/j.neo.2018.10.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Polymorphic Variant in p19Arf Confers Resistance to Chemically Induced Skin Tumors by Activating the p53 Pathway (2019)
  • Author(s): Saito M, Okumura K, Isogai E, Araki K, Tanikawa C, Matsuda K, Kamijo T, Kominami R, Wakabayashi Y.
  • Journal Title: Journal of Investigative Dermatology Volume: in press Issue: 7 Pages: 30032-6
  • DOI: 10.1016/j.jid.2018.12.027
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Recycling endosomal CD133 functions as an inhibitor of autophagy at the pericentrosomal region (2019)
  • Author(s): Hideki Izumi, Yuanyuan Li, Masami Shibaki, Daisuke Mori, Michio Yasunami, Seiji Sato, Hisashi Matsunaga, Takao Mae, Kenji Kodama, Takehiko Kamijo, Yasuhiko Kaneko & Akira Nakagawara
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 2236-2236
  • DOI: 10.1038/s41598-019-39229-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] EZH2 regulates neuroblastoma cell differentiation via NTRK1 promoter epigenetic modifications (2018)
  • Author(s): Li Zhenghao、Takenobu Hisanori、Setyawati Amallia Nuggetsiana、Akita Nobuhiro、Haruta Masayuki、Satoh Shunpei、Shinno Yoshitaka、Chikaraishi Koji、Mukae Kyosuke、Akter Jesmin、Sugino Ryuichi P.、Nakazawa Atsuko、Nakagawara Akira、Aburatani Hiroyuki、Ohira Miki、Kamijo Takehiko
  • Journal Title: Oncogene Volume: 37 Issue: 20 Pages: 2714-2727
  • DOI: 10.1038/s41388-018-0133-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Results of a phase II trial for high-risk neuroblastoma treatment protocol JN-H-07: a report from the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG) (2018)
  • Author(s): Hishiki T、For the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG)、Matsumoto K、Ohira M、Kamijo T、Shichino H、Kuroda T、Yoneda A、Soejima T、Nakazawa A、Takimoto T、Yokota I、Teramukai S、Takahashi H、Fukushima T、Kaneko T、Hara J、Kaneko M、Ikeda H、Tajiri T、Nakagawara A
  • Journal Title: International Journal of Clinical Oncology Volume: 23 Issue: 5 Pages: 965-973
  • DOI: 10.1007/s10147-018-1281-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of the genetic and clinical characteristics of neuroblastomas using genome-wide analysis (2017)
  • Author(s): Uryu K, Nishimura R, Kataoka K, Sato Y, Nakazawa A, Suzuki H, Yoshida K, Seki M, Hiwatari M, Isobe T, Shiraishi Y, Chiba K, Tanaka H, Miyano S, Koh K, Hanada R, Oka A, Hayashi Y, Ohira M, Kamijo T, Nagase H, Takimoto T, Tajiri T, Nakagawara A, Ogawa S, Takita J
  • Journal Title: Oncotarget Volume: 8 Issue: 64 Pages: 107513-107529
  • DOI: 10.18632/oncotarget.22495
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Neurocan, an extracellular chondroitin sulfate proteoglycan, stimulates neuroblastoma cells to promote malignant phenotypes. (2017)
  • Author(s): 1.Su Z, Kishida S, Tsubota S, Sakamoto K, Cao D, Kiyonari S, Ohira M, Kamijo T, Narita A, Xu Y, Takahashi Y, Kadomatsu K.
  • Journal Title: Oncotarget Volume: 8 Issue: 63 Pages: 106296-106310
  • DOI: 10.18632/oncotarget.22435
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Genomic analysis–integrated whole-exome sequencing of neuroblastomas identifies genetic mutations in axon guidance pathway (2017)
  • Author(s): Li Yuanyuan、Ohira Miki、Zhou Yong、Xiong Teng、Luo Wen、Yang Chao、Li Xiangchun、Gao Zhibo、Zhou Rui、Nakamura Yohko、Kamijo Takehiko、Kaneko Yasuhiko、Taketani Takeshi、Ueyama Junichi、Tajiri Tatsuro、Zhang Hongyan、Wang Jian、Yang Huanming、Yin Ye、Nakagawara Akira
  • Journal Title: Oncotarget Volume: 8 Issue: 34 Pages: 56684-56697
  • DOI: 10.18632/oncotarget.18079
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CFC1 is a cancer stemness-regulating factor in neuroblastoma (2017)
  • Author(s): Chikaraishi Koji、Takenobu Hisanori、Sugino Ryuichi P.、Mukae Kyosuke、Akter Jesmin、Haruta Masayuki、Kurosumi Masafumi、Endo Takaho A.、Koseki Haruhiko、Shimojo Naoki、Ohira Miki、Kamijo Takehiko
  • Journal Title: Oncotarget Volume: 8 Issue: 28 Pages: 45046-45059
  • DOI: 10.18632/oncotarget.18464
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Cancer-type OATP1B3 mRNA has the potential to become a detection and prognostic biomarker for human colorectal cancer. (2017)
  • Author(s): Sun Y, Harada M, Shimozato O, Souda H, Takiguchi N, Nabeya Y, Kamijo T, Akita H, Anzai N, Chiba K, Furihata T.
  • Journal Title: Biomark Med. Volume: 印刷中 Issue: 8 Pages: 629-639
  • DOI: 10.2217/bmm-2017-0098
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 1.Genome and epigenome profiling of high stage neuroblastoma (2018)
  • Author(s): Miki Ohira, Ryuichi Sugino, Hisanori Takenobu, Zhenghao Li, Masayuki Haruta, Genta Nagae, Claire Renard-Guillet, Akira Nakagawara, Hiroyuki Aburatani, Takehiko Kamijo
  • Organizer: AACR2018
  • Int'l Joint Research
• [Presentation] 2.CDX1 regulates neuroblastoma stemness through MYC pathway modulation and reprogramming gene activation (2018)
  • Author(s): Hisanori Takenobu, Miki Ohira, Ryuichi Sugino, Koji Chikaraishi, Kyosuke Mukae, Nobuhiro Akita, Masayuki Haruta, Akira Nakagawara, Manabu Nakayama, Haruhiko Koseki, Takehiko Kamijo
  • Organizer: ANR2018
  • Int'l Joint Research
• [Presentation] 3.Reevaluation of PDGFRα signal in neuroblastoma: high expression and a new nonsynonymous mutation (2018)
  • Author(s): Shunpei Satoh, Miki Ohira, Hisanori Takenobu, Akira Nakagawara, Takehiko Kamijo
  • Organizer: ANR2018
  • Int'l Joint Research
• [Presentation] 4.Genomic characterization of high-risk/ultra-high-risk neuroblastomas found in 610 patients registered in Japan Children’s Study Group Neuroblastoma Committee (JCCG-JNBSG) (2018)
  • Author(s): M Ohira, T Kamijo, R P Sugino, M Haruta, H Takenobu T Takimoto, A Nakazawa, T Hishiki, K Matsumoto, H Shichino, T Ushijima, T Iehara, Y Nakamura, H Nagase, J Takita, A Yoneda, Ti Fukushima, T Tajiri, A Nakagawara, Japan Children’s Cancer Group Neuroblastoma Committee (JCCG-JNBSG)
  • Organizer: ANR2018
  • Int'l Joint Research
• [Presentation] 5.CFC1 is a cancer stemness-regulating factor in neuroblastoma. (2018)
  • Author(s): Chikaraishi K, Takenobu H, Sugino RP, Mukae K, Akter J, Haruta M, Kurosumi M, Endo TA, Koseki H, Shimojo N, Ohira M, Kamijo T.
  • Organizer: ANR2018
  • Int'l Joint Research
• [Presentation] Effects of development regulators on neuroblastoma biology (2017)
  • Author(s): Takehiko Kamijo
  • Organizer: The 75th Annual Meeting of the Japanese Cancer Association
• [Remarks] 埼玉県立がんセンター 臨床腫瘍研究所
  • URL: https://www.pref.saitama.lg.jp/saitama-cc/kenkyujo/kenkyujo.html