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Development of eradicative cancer treatment based on synthetic lethality of induced cancer stem cells

Research Project

Project/Area Number 16H04701
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Tumor biology
Research InstitutionNational Cancer Center Japan

Principal Investigator

KIYONO Tohru  国立研究開発法人国立がん研究センター, 研究所, 分野長 (10186356)

Research Collaborator DENDO Kasimi  
GHANI Farhana lshrat  
YUGAWA Takashi  
NAKAHARA Tomomi  
YAMADA Kenji  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
Fiscal Year 2018: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000)
Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2016: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Keywordsがん幹細胞 / 合成致死 / RAS / マクロピノサイトーシス / MYC / 幹細胞 / 末梢型肺腺がん / 融合遺伝子 / 病理学 / ヒト正常細胞 / 癌 / methuosis
Outline of Final Research Achievements

By conditionally expressing a set of oncogenes in normal human epithelial cells, we established induced cancer stem cells as models of human cancers including pancreatic cancer and lung adenocarcinoma. Conditional expression of HPV16 E6E7, MYC and activated KRAS conferred highly tumorigenic potential to normal human epithelial cells, but halting expression of HPV16 E6E7 and MYC in the cells resulted in massive macro-pinocytotic cell death and loss of tumorigenicity. By conditional expression of a dominant-negative form of MYC (OmoMYC) in human cancer cell lines with mutant KRAS, including pancreatic cancer and lung adenocarcinoma, resulted in macropinocytotic cell death. The results suggest suppression of MYC can induce synthetic lethality to human cancer cells with active mutation of RAS family genes.

Academic Significance and Societal Importance of the Research Achievements

RASは全がんの30%で活性型変異が見つかるが、RASを標的とした分子標的薬はいまだに開発されていない。また、変異RASの遺伝子増幅ががんの浸潤転移を促進し変異RASの発現量の増加ががんの増悪にかかわっている。RASに変異を持つがんではMYCの高発現によりその造腫瘍性を支えておりMYC発現の低い細胞に変異RASを発現させると過剰なマクロピノサイトーシスによる細胞死がもたらされることを示した。変異RASを持つがん、特に悪性度の高い変異RASを高発現するがんではMYCの機能を抑えることで合成致死をもたらす治療が有効であることが明らかになり、RASに変異のあるがんに対する治療戦略を示すことができた。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (9 results)

All 2019 2018 2017 Other

All Journal Article (1 results) (of which Peer Reviewed: 1 results,  Open Access: 1 results) Presentation (5 results) (of which Invited: 2 results) Remarks (1 results) Patent(Industrial Property Rights) (2 results) (of which Overseas: 1 results)

  • [Journal Article] Induction of non-apoptotic programmed cell death by oncogenic RAS in human epithelial cells and its suppression by MYC overexpression.2018

    • Author(s)
      Dendo K, Yugawa T, Nakahara T, Ohno SI, Goshima N, Arakawa H, Kiyono T.
    • Journal Title

      Carcinogenesis

      Volume: 39 Issue: 2 Pages: 202-213

    • DOI

      10.1093/carcin/bgx124

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed / Open Access
  • [Presentation] 至適培養法によるヒト正常上皮細胞の培養とがん研究への応用2019

    • Author(s)
      清野透
    • Organizer
      H30年度北大遺制研シンポジウム「感染・免疫・がん・炎症」
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] ヒト正常細胞の不死化とがん化2019

    • Author(s)
      清野透
    • Organizer
      千葉糖尿病内分泌・骨代謝疾患診療ネットワーク講演会2019
    • Related Report
      2018 Annual Research Report
    • Invited
  • [Presentation] An efficient method to establish ovarian cancer cell lines recapitulating features of primary tumors2018

    • Author(s)
      Farhana Ishrat Ghani , Kasumi Dendo, Yuki Yoshimatsu, Kazuaki Takahashi, Takashi Kohno, Reiko Watanabe, Hiroshi Yoshida, Masayuki Yoshida, Mitsuya Ishikawa, Tomoyasu Kato and Tohru Kiyono
    • Organizer
      第2回がん三次元培養研究会
    • Related Report
      2018 Annual Research Report
  • [Presentation] 新規プログラム細胞死メスオーシスによるがん抑制機構2018

    • Author(s)
      清野透
    • Organizer
      北海道大学遺伝子病制御研究所「感染、免疫、がん、炎症」研究集会
    • Related Report
      2017 Annual Research Report
  • [Presentation] Induction of Macropinocytic Cell Death by Oncogenic RAS in Human Epithelial Cells and Its Suppression by MYC Overexpression2017

    • Author(s)
      Dendo K, Yugawa T, Nakahara T, Ohno SI, Goshima N, Arakawa H, Kiyono T.
    • Organizer
      分子生物学会年会
    • Related Report
      2017 Annual Research Report
  • [Remarks] 国立がんセンター研究所 発がん・予防研究分野HP

    • URL

      http://www.nccri.ncc.go.jp/s003/

    • Related Report
      2016 Annual Research Report
  • [Patent(Industrial Property Rights)] 特願2018-2304742019

    • Inventor(s)
      片山雅史、清野透、福田智一
    • Industrial Property Rights Holder
      岩手大学
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2018 Annual Research Report
  • [Patent(Industrial Property Rights)] PCT/JP2018/ 0483082019

    • Inventor(s)
      梅澤 明弘、清野 透
    • Industrial Property Rights Holder
      国立成育医療研究センター、国立がん研究センター
    • Industrial Property Rights Type
      特許
    • Filing Date
      2019
    • Related Report
      2018 Annual Research Report
    • Overseas

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Published: 2016-04-21   Modified: 2021-01-27  

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