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Autophagy provides a quiescent state in colon cancer stem cells

Research Project

Project/Area Number 20K09023
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 55020:Digestive surgery-related
Research InstitutionTeikyo University (2022)
National Cancer Center Japan (2020-2021)

Principal Investigator

Ohata Hirokazu  帝京大学, 先端総合研究機構, 講師 (40570057)

Project Period (FY) 2020-04-01 – 2023-03-31
Project Status Completed (Fiscal Year 2022)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsがん幹細胞
Outline of Research at the Start

大腸がん組織において、「がん幹細胞」を頂点とした階層性が存在し、高い造腫瘍能や治療抵抗性を有するがん幹細胞が、がんの再発・転移に深く関与していると考えられている。それ故、大腸がんの治療抵抗性を克服する方法として、がん幹細胞を標的とした治療法の開発が強く望まれている。また、大腸がんには増殖型と静止型のがん幹細胞が存在し、抗がん剤に抵抗性を示すのは静止型のがん幹細胞であることが示唆されている。そこで、本研究はオートファジー活性化による静止期大腸がん幹細胞の維持機構を解明し、静止期大腸がん幹細胞を標的とした治療薬の開発に繋げることを目的とする。

Outline of Final Research Achievements

Cancer tissue represent the intratumoral heterogeneity, and the resistance to anti-cancer therapy is often attributed to slow-cycling persister populations with cancer stem cell (CSC)-like features. We previously identified the heterogeneity in colon CSCs from patient-derived organoids and xenografted tumors and demonstrated that while the NOX1-mTORC1 pathway is responsible for proliferation of a fast-cycling population of cancer cells, PROX1 expression is required for a persister-like slow-cycling population of CSCs. Here we demonstrated that enhanced autophagic activity mediated by mTORC1 inhibition induced PROX1 expression. Induction of PROX1 in turn inhibited NOX1-mediated mTORC1 activation, thus providing the quiescent state via a feedback regulation. Inhibition of autophagy synergized with mTORC1 inhibition to block cancer proliferation.

Academic Significance and Societal Importance of the Research Achievements

大腸がんの根治を目指すためには、治療抵抗性を担う大腸がん細胞を特定し、その細胞を標的とした新しい治療法の開発が強く望まれている。本研究により、静止期にあるがん幹細胞がオートファジー活性が高く、抗がん剤に強い抵抗性を示すことが明らかとなった。また、大腸がんに対する既存の抗がん剤とオートファジー阻害剤の併用により、相乗的に大腸がん細胞の増殖を抑制することがわかった。以上の研究成果は、大腸がんの治療抵抗性の克服、ひいては大腸がんの根治への道標となると考えられる。

Report

(4 results)
  • 2022 Annual Research Report   Final Research Report ( PDF )
  • 2021 Research-status Report
  • 2020 Research-status Report
  • Research Products

    (6 results)

All 2022 2021 2020

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 3 results) Presentation (1 results) Book (1 results)

  • [Journal Article] NF-κB suppression synergizes with E7386, an inhibitor of CBP/β-catenin interaction, to block proliferation of patient-derived colon cancer spheroids2022

    • Author(s)
      Kanda Y, Ohata H, Miyazaki T, Sakai H, Mori Y, Shiokawa D, Yokoi A, Owa T, Ochiai A, *Okamoto K.
    • Journal Title

      Biochem. Biophys. Res. Commun.

      Volume: 586 Pages: 93

    • DOI

      10.1016/j.bbrc.2021.11.063

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Stemness and immune evasion conferred by the TDO2-AHR pathway are associated with liver metastasis of colon cancer2022

    • Author(s)
      Miyazaki T, Chung S, Sakai H, Ohata H, Obata Y, Shiokawa D, Mizoguchi Y, Kubo T, Ichikawa H, Taniguchi H, Aoki K, Soga T, Nakagama H, *Okamoto K.
    • Journal Title

      Cancer Sci.

      Volume: 113 Issue: 1 Pages: 170

    • DOI

      10.1111/cas.15182

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Establishment of in vitro 3D spheroid cell cultivation from human gynecologic cancer tissues2021

    • Author(s)
      Ueda Haruka、Mori Yutaro、Yamawaki Kaoru、Ishiguro Tatsuya、Ohata Hirokazu、Sato Ai、Sugino Kentaro、Yachida Nozomi、Yamaguchi Manako、Suda Kazuaki、Tamura Ryo、Yoshihara Kosuke、Okamoto Koji、Enomoto Takayuki
    • Journal Title

      STAR Protocols

      Volume: 2 Issue: 1 Pages: 100354-100354

    • DOI

      10.1016/j.xpro.2021.100354

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Slow-cycling cancer stem cells regulate progression and chemoresistance in colon cancer2020

    • Author(s)
      Shiokawa Daisuke、Sakai Hiroaki、Ohata Hirokazu、Miyazaki Toshiaki、Kanda Yusuke、Sekine Shigeki、Narushima Daichi、Hosokawa Masahito、Kato Mamoru、Suzuki Yutaka、Takeyama Haruko、Kambara Hideki、Nakagama Hitoshi、Okamoto Koji
    • Journal Title

      Cancer Research

      Volume: 80 Issue: 20 Pages: 4451

    • DOI

      10.1158/0008-5472.can-20-0378

    • Related Report
      2020 Research-status Report
    • Peer Reviewed
  • [Presentation] PROX1 induction by autophagy provides a persister-like state via repression of NOX1-mTORC1 pathway in colon cancer cells2022

    • Author(s)
      Hirokazu Ohata, Daisuke Shiokawa, Koji Okamoto
    • Organizer
      第81回日本癌学会
    • Related Report
      2022 Annual Research Report
  • [Book] 治療標的としてのがん幹細胞2020

    • Author(s)
      伊藤 貴浩、大畑 広和
    • Total Pages
      128
    • Publisher
      医歯薬出版株式会社
    • Related Report
      2020 Research-status Report

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Published: 2020-04-28   Modified: 2024-01-30  

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