Analysis of the regulation mechanisms of colorectal cancer stem cell maintenance and plasticity

• Project/Area Number: 18K07337
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Japanese Foundation for Cancer Research
• Principal Investigator: MASHIMA Tetsuo 公益財団法人がん研究会, がん化学療法センター 分子生物治療研究部, 主任研究員 (30311228)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: がん幹細胞 / 可塑性 / 大腸がん / c-KIT / タンキラーゼ / CD44

Outline of Final Research Achievements

We identified tankyrase, a poly(ADP-ribose) polymerase member, as a mediator of colorectal cancer stem cell maintenance. Furthermore, we showed that the AXIN-dependent regulation of c-KIT tyrosine kinase expression is a critical step in the cancer stem cell maintenance downstream of tankyrase. These data suggest that the inhibition of cancer stem cell fraction by targeting tankyrase could be a new strategy to enhance the effect of cancer chemotherapy.

Academic Significance and Societal Importance of the Research Achievements

薬物療法初期の治療抵抗性に関わるとされるがん幹細胞の安定維持や可塑性制御に寄与する新たな分子経路が見出された。また同経路を標的とする新たな分子標的薬剤が明らかになり、大腸がんの治療抵抗性や再発を抑えるための新しい方法が示唆された。

Research Products

• [Journal Article] c-KIT regulates stability of cancer stemness in CD44-positive colorectal cancer cells (2020)
  • Author(s): Tomizawa Fumiya、Jang Myung-Kyu、Mashima Tetsuo、Seimiya Hiroyuki
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 527 Issue: 4 Pages: 1014-1020
  • DOI: 10.1016/j.bbrc.2020.05.024
  • Peer Reviewed
• [Journal Article] Serum IL-8 level as a candidate prognostic marker of response to anti-angiogenic therapy for metastatic colorectal cancer (2020)
  • Author(s): Suenaga Mitsukuni、Mashima Tetsuo、Kawata Naomi、Wakatsuki Takeru、Dan Shingo、Seimiya Hiroyuki、Yamaguchi Kensei
  • Journal Title: International Journal of Colorectal Disease Volume: 36 Issue: 1 Pages: 131-139
  • DOI: 10.1007/s00384-020-03748-y
  • Peer Reviewed
• [Journal Article] ALDH1A3-mTOR axis as a therapeutic target for anticancer drug-tolerant persister cells in gastric cancer. (2020)
  • Author(s): Kawakami R, Mashima T, Kawata N, Kumagai K, Migita T, Sano T, Mizunuma N, Yamaguchi K, Seimiya H
  • Journal Title: Cancer Sci Volume: 111 Issue: 3 Pages: 962-973
  • DOI: 10.1111/cas.14316
  • Peer Reviewed / Open Access
• [Journal Article] Tankyrase Inhibitors Target Colorectal Cancer Stem Cells via AXIN-Dependent Downregulation of c-KIT Tyrosine Kinase. (2020)
  • Author(s): Jang MK, Mashima T, Seimiya H
  • Journal Title: Mol Cancer Ther Volume: 19 Issue: 3 Pages: 765-776
  • DOI: 10.1158/1535-7163.mct-19-0668
  • Peer Reviewed
• [Journal Article] Epidermal growth factor receptor mRNA expression: A potential molecular escape mechanism from regorafenib (2020)
  • Author(s): Matsusaka Satoshi、Hanna Diana L.、Ning Yan、Yang Dongyun、Cao Shu、Berger Martin D.、Miyamoto Yuji、Suenaga Mitsukuni、Dan Shingo、Mashima Tetsuo、Seimiya Hiroyuki、Zhang Wu、Lenz Heinz‐Josef
  • Journal Title: Cancer Science Volume: 111 Issue: 2 Pages: 441-450
  • DOI: 10.1111/cas.14273
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] In silico chemical screening identifies epidermal growth factor receptor as a therapeutic target of drug-tolerant CD44v9-positive gastric cancer cells. (2019)
  • Author(s): Mashima T, Iwasaki R, Kawata N, Kawakami R, Kumagai K, Migita T, Sano T, Yamaguchi K, Seimiya H
  • Journal Title: Br J Cancer Volume: 121 Issue: 10 Pages: 846-856
  • DOI: 10.1038/s41416-019-0600-9
  • Peer Reviewed
• [Journal Article] Meeting report of the 14th Japan Korea joint symposium on cancer and aging research: current status of translational research and approaches to precision medicine (2019)
  • Author(s): Sueoka Eisaburo、Watanabe Tatsuro、Mashima Tetsuo、Shirakami Yohei、Komori Atsumasa、Matsuo Keitaro、Yoshikawa Hiroshi Y.、Cho Kyung A、Park Tae Jun、Seimiya Hiroyuki、Kim Eung-Gook、Suganuma Masami、Chung Junho
  • Journal Title: Journal of Cancer Research and Clinical Oncology Volume: 印刷中 Issue: 5 Pages: 1263-1271
  • DOI: 10.1007/s00432-019-02887-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A phase I study to determine the maximum tolerated dose of trifluridine/tipiracil and oxaliplatin in patients with refractory metastatic colorectal cancer: LUPIN study (2019)
  • Author(s): Suenaga Mitsukuni、Wakatsuki Takeru、Mashima Tetsuo、Ogura Mariko、Ichimura Takashi、Shinozaki Eiji、Nakayama Izuma、Osumi Hiroki、Ota Yumiko、Takahari Daisuke、Chin Keisho、Seimiya Hiroyuki、Yamaguchi Kensei
  • Journal Title: Investigational New Drugs Volume: 印刷中 Issue: 1 Pages: 2567-2575
  • DOI: 10.1007/s10637-019-00749-9
  • Peer Reviewed / Open Access
• [Journal Article] Gene Polymorphisms in the CCL5/CCR5 Pathway as a Genetic Biomarker for Outcome and Hand-Foot Skin Reaction in Metastatic Colorectal Cancer Patients Treated With Regorafenib. (2018)
  • Author(s): Suenaga M, Schirripa M, Cao S, Zhang W, Yang D, Ning Y, Cremolini C, Antoniotti C, Borelli B, Mashima T, Okazaki S, Berger MD, Miyamoto Y, Gopez R Jr., Barzi A, Lonardi S, Yamaguchi T, Falcone A, Loupakis F, Lenz HJ
  • Journal Title: Clin Colorectal Cancer Volume: 印刷中 Issue: 2 Pages: e395-e414
  • DOI: 10.1016/j.clcc.2018.02.010
  • Peer Reviewed / Int'l Joint Research
• [Presentation] ALDH1A3 as a marker and therapeutic target for residual gastric cancer cells after anticancer drug treatment. (2020)
  • Author(s): Tetsuo Mashima, Ryuhei Kawakami, Koshi Kumagai, Toshiro Migita, Takeshi Sano, Kensei Yamaguchi, Hiroyuki Seimiya
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] c-KIT maintains CD44-positive colorectal cancer stem cells. (2020)
  • Author(s): Tomizawa F, Jang MK, Mashima T, Seimiya H
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] ALDH1A3は制がん剤処理後の残存胃がん細胞で発現亢進し、増殖と造腫瘍性に寄与する (2020)
  • Author(s): 馬島哲夫、川上隆兵、清宮啓之
  • Organizer: 第24回日本がん分子標的治療学会学術集会
• [Presentation] shRNAスクリーニングによる大腸がん幹細胞の新規治療標的分子の探索 (2020)
  • Author(s): 森野峻、馬島哲夫、吉田稔、清宮啓之
  • Organizer: 第24回日本がん分子標的治療学会学術集会
• [Presentation] 受容体型チロシンキナーゼc-KITによる大腸がん幹細胞性の維持 (2020)
  • Author(s): 冨澤文弥、張明キュ、馬島哲夫、清宮啓之
  • Organizer: 第24回日本がん分子標的治療学会学術集会
• [Presentation] EGFR inhibitors suppress drug-tolerant CD44v+ gastric cancer cell growth and enhance the antitumor effect of irinotecan (2019)
  • Author(s): Tetsuo Mashima, Risa Iwasaki, Ryuhei Kawakami, Koshi Kumagai, Toshiro Migita, Takeshi Sano, Kensei Yamaguchi, Hiroyuki Seimiya
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] Tankyrase Inhibitors target colorectal cancer stem-like cells through an AXIN-dependent mechanisms (2019)
  • Author(s): Jang MK, Mashima T, Seimiya H
  • Organizer: 第78回日本癌学会学術総会
• [Presentation] EGFR阻害剤は胃がん薬剤抵抗性に寄与するCD44v発現細胞の増殖を抑制し、イリノテカンの治療効果を増強する (2019)
  • Author(s): 馬島哲夫 , 岩崎里紗, 川上隆兵, 清宮啓之
  • Organizer: 第23回日本がん分子標的治療学会学術集会
• [Presentation] タンキラーゼ阻害剤による大腸がん幹細胞の増殖抑制とその分子機序 (2019)
  • Author(s): 張明きゅ、馬島哲夫 , 清宮啓之
  • Organizer: 第23回日本がん分子標的治療学会学術集会
• [Presentation] 胃がんの薬剤耐性に寄与するCD44v陽性細胞を標的とする化合物のin silico探索 (2018)
  • Author(s): 馬島哲夫 , 岩崎里紗, 川上隆兵, 清宮啓之 他
  • Organizer: 第22回日本がん分子標的治療学会学術集会
• [Presentation] Targeting colorectal cancer stem-like CD44-positive cells by tankyrase inhibitors (2018)
  • Author(s): Tetsuo Mashima, Myungkyu Jang, Hiroyuki Seimiya
  • Organizer: 14th Japan-Korea Joint Symposium on Cancer and Aging Research
  • Int'l Joint Research / Invited
• [Presentation] In silico screening for agents targeting drug-tolerant CD44v-positive cells in patient-derived gastric cancer. (2018)
  • Author(s): Tetsuo Mashima, Risa Iwasaki, Koshi Kumagai, Ryuhei Kawakami, Takeshi Sano, Kensei Yamaguchi, Hiroyuki Seimiya
  • Organizer: 第77回日本癌学会学術総会
• [Presentation] Targeting colorectal cancer stem cells by tankyrase inhibition (2018)
  • Author(s): Tetsuo Mashima, Hiroyuki Seimiya
  • Organizer: 第41回日本分子生物学会年会
  • Invited
• [Book] 別冊 医学のあゆみ 治療標的としてのがん幹細胞「がん幹細胞と薬剤耐性」 (2021)
  • Author(s): 馬島哲夫、清宮啓之
  • Total Pages: 6
  • Publisher: 医歯薬出版
• [Book] 進化するがん創薬 (2019)
  • Author(s): 清宮啓之 編
  • Total Pages: 324
  • Publisher: 化学同人
  • ISBN: 9784759817331