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The mechanisms of BMP-EGFR cross talk in colorectal organoids

Research Project

Project/Area Number 21K07942
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 53010:Gastroenterology-related
Research InstitutionOsaka University

Principal Investigator

Jumpei Kondo  大阪大学, 大学院医学系研究科, 准教授 (80624593)

Co-Investigator(Kenkyū-buntansha) 井上 正宏  京都大学, 医学研究科, 特定教授 (10342990)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2023: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords大腸癌 / EGFR / オルガノイド / BMP / LRIG1 / バイオマーカー / BMP4 / 大腸がん / MEK阻害 / 多様性
Outline of Research at the Start

EGFR/MEK/ERKは大腸癌分子標的治療の中心となる重要なシグナル経路であるが、これらを標的とした治療の臨床的効果はまだ十分ではない。申請者らはこれまでに新しい癌オルガノイド培養系CTOS法を開発し、患者由来の癌細胞におけるシグナル経路の活性化、およびその患者間の多様性を検討してきた。その中で、BMP/SMAD経路とEGFR/MEK経路にこれまで報告のないクロストークが存在することを見出した。本申請の研究ではBMP/SMAD経路の活性化がEGFRシグナルを補助する機序の詳細と多様性を明らかにする。

Outline of Final Research Achievements

The BMP pathway affects colorectal cancer (CRC) cells differently than normal cells, sometimes promoting tumor growth and other times suppressing it. We found that CRC cells reside in a BMP-rich environment. Inhibiting BMP with LDN193189 slows CRC organoid growth by reducing EGFR levels through LRIG1-mediated protein degradation. In CRC organoids, BMP inhibition induces LRIG1 expression, which correlates with growth suppression. Knocking down LRIG1 rescued LDN193189-mediated growth inhibition. Combining LDN193189 with trametinib, a MEK inhibitor, cooperatively inhibited CRC growth in vitro and in vivo. These results suggest that simultaneous BMP and MEK inhibition could be a promising CRC treatment. Studying LRIG1 induction and growth suppression in patient-derived organoids may help identify potential responders to this therapy.

Academic Significance and Societal Importance of the Research Achievements

BMP阻害剤は良性疾患である炎症性貧血の治療薬として臨床試験が行われており、抗腫瘍薬よりも副作用は低レベルであると考えられる。このような薬剤が抗腫瘍薬の効果を増強する目的で用いることができれば、がん治療の選択肢は大きく広がる。今回の検討では、BMP阻害剤の効果が期待できる症例を選択する機能的バイオマーカーの開発も同時に進めることができたため、将来的に臨床試験を行う段階に至った場合も高い成功率が期待できる。

Report

(4 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • 2021 Research-status Report
  • Research Products

    (12 results)

All 2023 2022 2021 Other

All Int'l Joint Research (2 results) Journal Article (8 results) (of which Int'l Joint Research: 2 results,  Peer Reviewed: 7 results,  Open Access: 6 results) Presentation (2 results)

  • [Int'l Joint Research] Vanderbilt University(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] Vanderbilt University(米国)

    • Related Report
      2022 Research-status Report
  • [Journal Article] Inhibition of the bone morphogenetic protein pathway suppresses tumor growth through downregulation of epidermal growth factor receptor in <scp>MEK</scp>/<scp>ERK</scp>‐dependent colorectal cancer2023

    • Author(s)
      Shimizu Shota、Kondo Jumpei、Onuma Kunishige、Coppo Roberto、Ota Kasumi、Kamada Mayumi、Harada Yohei、Tanaka Yoshihisa、Nakazawa Mai Adachi、Tamada Yoshinori、Okuno Yasushi、Kawada Kenji、Obama Kazutaka、Coffey Robert J.、Fujiwara Yoshiyuki、Inoue Masahiro
    • Journal Title

      Cancer Science

      Volume: 114 Issue: 9 Pages: 3636-3648

    • DOI

      10.1111/cas.15882

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Prohaptoglobin is a possible prognostic biomarker for colorectal cancer2023

    • Author(s)
      Morishita Koichi、Kondo Jumpei、Sakon Daisuke、Hayashibara Ayumu、Tamura Ikumi、Shimizu Kayoko、Takamatsu Shinji、Murata Kohei、Kamada Yoshihiro、Miyoshi Eiji
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 672 Pages: 72-80

    • DOI

      10.1016/j.bbrc.2023.06.017

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Hepatocyte differentiation from mouse liver ductal organoids by transducing 4 liver-specific transcription factors2023

    • Author(s)
      Tomofuji Katsuhiro、Kondo Jumpei、Onuma Kunishige、Coppo Roberto、Horie Hiroshi、Oyama Koki、Miyoshi Eiji、Fukumitsu Ken、Ishii Takamichi、Hatano Etsuro、Inoue Masahiro
    • Journal Title

      Hepatology Communications

      Volume: 7 Issue: 5

    • DOI

      10.1097/hc9.0000000000000134

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Distinct but interchangeable subpopulations of colorectal cancer cells with different growth fates and drug sensitivity2023

    • Author(s)
      Coppo Roberto、Kondo Jumpei、Iida Keita、Okada Mariko、Onuma Kunishige、Tanaka Yoshihisa、Kamada Mayumi、Ohue Masayuki、Kawada Kenji、Obama Kazutaka、Inoue Masahiro
    • Journal Title

      iScience

      Volume: 26 Issue: 2 Pages: 105962-105962

    • DOI

      10.1016/j.isci.2023.105962

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Inhibition of the BMP pathway suppresses tumor growth via downregulation of EGFR in MEK/ERK-dependent colorectal cancer2022

    • Author(s)
      Shimizu Shota、Kondo Jumpei、Onuma Kunishige、Ota Kasumi、Kamada Mayumi、Harada Yohei、Tanaka Yoshihisa、Nakazawa Mai Adachi、Tamada Yoshinori、Okuno Yasushi、Kawada Kenji、Obama Kazutaka、Coffey Robert J、Fujiwara Yoshiyuki、Inoue Masahiro
    • Journal Title

      BioRxiv

      Volume: NA

    • DOI

      10.1101/2022.11.01.514643

    • Related Report
      2022 Research-status Report
    • Open Access / Int'l Joint Research
  • [Journal Article] Polarity switching of ovarian cancer cell clusters via <scp>SRC</scp> family kinase is involved in the peritoneal dissemination2022

    • Author(s)
      Kawata Mayuko、Kondo Jumpei、Onuma Kunishige、Ito Yu、Yokoi Takeshi、Hamanishi Junzo、Mandai Masaki、Kimura Tadashi、Inoue Masahiro
    • Journal Title

      Cancer Science

      Volume: 113 Issue: 10 Pages: 3437-3448

    • DOI

      10.1111/cas.15493

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Lewis glycosphingolipids as critical determinants of TRAIL sensitivity in cancer cells2022

    • Author(s)
      Fukuoka Tomoya、Moriwaki Kenta、Takamatsu Shinji、Kondo Jumpei、Tanaka-Okamoto Miki、Tomioka Azusa、Semba Manami、Komazawa-Sakon Sachiko、Kamada Yoshihiro、Kaji Hiroyuki、Miyamoto Yasuhide、Inoue Masahiro、Bessho Kazuhiko、Miyoshi Yoko、Ozono Keiichi、Nakano Hiroyasu、Miyoshi Eiji
    • Journal Title

      Oncogene

      Volume: 41 Issue: 38 Pages: 4385-4396

    • DOI

      10.1038/s41388-022-02434-3

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Aberrant activation of <scp>Rho</scp> / <scp>ROCK</scp> signaling in impaired polarity switching of colorectal micropapillary carcinoma2021

    • Author(s)
      Onuma Kunishige、Sato Yumi、Okuyama Hiroaki、Uematsu Hiroyuki、Homma Keiichiro、Ohue Masayuki、Kondo Jumpei、Inoue Masahiro
    • Journal Title

      The Journal of Pathology

      Volume: 255 Issue: 1 Pages: 84-94

    • DOI

      10.1002/path.5748

    • Related Report
      2021 Research-status Report
    • Peer Reviewed
  • [Presentation] Subpopulations with distinct and interchangeable capacity of spheroid formation and growth in colorectal cancer2022

    • Author(s)
      Roberto Coppo, Jumpei Kondo, Kunishige Onuma, Masahiro Inoue
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Research-status Report
  • [Presentation] BMP inhibition suppresses colorectal cancer growth via negative regulation of EGFR2021

    • Author(s)
      Shota Shimizu, Jumpei Kondo and Masahiro Inoue
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Research-status Report

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Published: 2021-04-28   Modified: 2025-01-30  

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