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Developing mouse models of inflammation-driven invasive gastric cancer to reveal novel therapeutic targets

Research Project

Project/Area Number 17H01399
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Research Field Tumor biology
Research InstitutionKanazawa University

Principal Investigator

Barker Nicholas  金沢大学, その他部局等, リサーチ・プロフェッサー (30787651)

Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥42,380,000 (Direct Cost: ¥32,600,000、Indirect Cost: ¥9,780,000)
Fiscal Year 2019: ¥13,000,000 (Direct Cost: ¥10,000,000、Indirect Cost: ¥3,000,000)
Fiscal Year 2018: ¥13,910,000 (Direct Cost: ¥10,700,000、Indirect Cost: ¥3,210,000)
Fiscal Year 2017: ¥15,470,000 (Direct Cost: ¥11,900,000、Indirect Cost: ¥3,570,000)
KeywordsGastric cancer / Mouse model / Inflammation / Lgr5 / Organoid / gastric cancer / mouse model / inflammation / organoid / 癌 / 再生医療 / 細胞・組織 / 発現制御 / 遺伝子 / 再生医学
Outline of Final Research Achievements

There is an urgent, unmet need for accurate mouse models of invasive, metastatic gastric cancer that can be used to derive important mechanistic insight into gastric cancer progression and to identify candidate cancer stem cell populations as novel therapeutic targets. We generated the first inflammation-driven mouse models of invasive gastric cancer for use in studying gastric cancer development in the stomach, with a particular focus on understanding the role of Lgr5+ stem cells and Lgr5+ cancer stem cells in this process.
These mouse models will also be invaluable as screening modalities for accurately evaluating the efficacy/selectivity of future anti-cancer therapeutics. The mouse models and experimental procedures detailed here are original and will deliver results that are expected to have a major impact on the gastric cancer research field.

Academic Significance and Societal Importance of the Research Achievements

胃がんの発生機序に対する私たち理解は限られており、このことが効果的な治療法の開発を妨げている。我々は、炎症を伴って発生するヒト胃がんを模倣する新たな胃がんマウスモデルを樹立し、生体内・生体外の解析を通してLgr5遺伝子を発現する胃がん細胞が、がん幹細胞である可能性を示唆する結果を得た。また、胃がんの悪性化に寄与する新たなドライバー変異を持つマウスモデルを作製し、それらの遺伝子変異が胃がんの進展に与える影響を解析した。これらの研究手法や得られた結果は、胃がんの進行を制御するメカニズムの迅速な解明や胃がんに対する新たな治療法の開発につながることが期待される。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Annual Research Report
  • 2017 Annual Research Report
  • Research Products

    (15 results)

All 2020 2019 2018 2017 Other

All Int'l Joint Research (1 results) Journal Article (11 results) (of which Int'l Joint Research: 6 results,  Peer Reviewed: 11 results,  Open Access: 1 results) Remarks (3 results)

  • [Int'l Joint Research] A*Star(シンガポール)

    • Related Report
      2017 Annual Research Report
  • [Journal Article] AQP5 enriches for stem cells and cancer origins in the distal stomach2020

    • Author(s)
      Tan Si Hui、Barker Nick et al.
    • Journal Title

      Nature

      Volume: 578 Issue: 7795 Pages: 437-443

    • DOI

      10.1038/s41586-020-1973-x

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Frizzled-7 Is Required for Wnt Signaling in Gastric Tumors with and Without Apc Mutations2019

    • Author(s)
      Flanagan Dustin J.、Barker Nick、Costanzo Natasha S. Di、Mason Elizabeth A.、Gurney Austin、Meniel Valerie S.、Koushyar Sarah、Austin Chloe R.、Ernst Matthias、Pearson Helen B.、Boussioutas Alex、Clevers Hans、Phesse Toby J.、Vincan Elizabeth
    • Journal Title

      Cancer Research

      Volume: 79 Issue: 5 Pages: 970-981

    • DOI

      10.1158/0008-5472.can-18-2095

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] A contemporary snapshot of intestinal stem cells and their regulation2019

    • Author(s)
      Seishima Ryo、Barker Nick
    • Journal Title

      Differentiation

      Volume: 108 Pages: 3-7

    • DOI

      10.1016/j.diff.2019.01.004

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Bortezomib Stabilizes and Activates p53 in Proliferative Compartments of Both Normal and Tumor Tissues In Vivo2019

    • Author(s)
      Xue Yuezhen、Barker Nick、Hoon Shawn、He Pingping、Thakur Teena、Abdeen Shifana Raja、Maruthappan Priadarsini、Ghadessy Farid J.、Lane David P.
    • Journal Title

      Cancer Research

      Volume: 79 Issue: 14 Pages: 3595-3607

    • DOI

      10.1158/0008-5472.can-18-3744

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Distinct Localization of Mature HGF from its Precursor Form in Developing and Repairing the Stomach.2019

    • Author(s)
      Jangphattananont N, Sato H, Imamura R, Sakai K, Terakado Y, Murakami K, Barker N, Oshima H, Oshima M, Takagi J, Kato Y, Yano S, Matsumoto K
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 12 Issue: 12 Pages: 2955-2955

    • DOI

      10.3390/ijms20122955

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The Function of Lgr5+ Cells in the Gastric Antrum Does Not Require Fzd7 or Myc In Vivo2019

    • Author(s)
      Flanagan Dustin、Barker Nick、Ernst Matthias、Vincan Elizabeth、Phesse Toby
    • Journal Title

      Biomedicines

      Volume: 7 Issue: 3 Pages: 50-50

    • DOI

      10.3390/biomedicines7030050

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Neonatal Wnt-dependent Lgr5 positive stem cells are essential for uterine gland development2019

    • Author(s)
      Seishima Ryo、Leung Carly、Yada Swathi、Murad Katzrin Bte Ahmed、Tan Liang Thing、Hajamohideen Amin、Tan Si Hui、Itoh Hideki、Murakami Kazuhiro、Ishida Yoshihiro、Nakamizo Satoshi、Yoshikawa Yusuke、Wong Esther、Barker Nick
    • Journal Title

      Nature Communications

      Volume: 10 Issue: 1 Pages: 1-17

    • DOI

      10.1038/s41467-019-13363-3

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] RSPO2 inhibition of RNF43 and ZNRF3 governs limb development independently of LGR4/5/62018

    • Author(s)
      Szenker-Ravi Emmanuelle、Altunoglu Umut、Leushacke Marc at al.
    • Journal Title

      Nature

      Volume: 557 Issue: 7706 Pages: 564-569

    • DOI

      10.1038/s41586-018-0118-y

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Recent Advances in Lgr5 + Stem Cell Research2018

    • Author(s)
      Leung Carly、Tan Si Hui、Barker Nick
    • Journal Title

      Trends in Cell Biology

      Volume: 28 Issue: 5 Pages: 380-391

    • DOI

      10.1016/j.tcb.2018.01.010

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Stem cells in 2017: Digesting recent stem cell advances in the gut2018

    • Author(s)
      Barker Nick
    • Journal Title

      Nature Reviews Gastroenterology & Hepatology

      Volume: 15 Issue: 2 Pages: 78-80

    • DOI

      10.1038/nrgastro.2017.176

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Lgr5-Expressing Chief Cells Drive Epithelial Regeneration and Cancer in the Oxyntic Stomach.2017

    • Author(s)
      Leushacke M, Tan SH, Wong A, Yada S, Hajamohideen A, Tan LT, Goh J, Wong E, Denil SL, Murakami K & Barker N
    • Journal Title

      Nature Cell Biology

      Volume: 7 Issue: 7 Pages: 774-786

    • DOI

      10.1038/ncb3541

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Remarks] がんの起源となるヒト胃組織幹細胞の特定に世界で初めて成功!

    • URL

      https://www.kanazawa-u.ac.jp/rd/75854

    • Related Report
      2019 Annual Research Report
  • [Remarks] 新生児期の子宮に存在するWnt依存性のLgr5陽性幹細胞は子宮腺の発生に必須である

    • URL

      http://ganken.cri.kanazawa-u.ac.jp/wp-content/uploads/2019/11/20191129_Murakami_NarureCommunications-1.pdf

    • Related Report
      2019 Annual Research Report
  • [Remarks] 傷の修復と発がんは紙一重?

    • URL

      http://ganken.cri.kanazawa-u.ac.jp/wp-content/uploads/2017/06/20170605.pdf

    • Related Report
      2019 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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