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Investigation of cell-cell adhesion structures and signaling pathways causing collective invasion in cancer cells

Research Project

Project/Area Number 21K07142
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 50010:Tumor biology-related
Research InstitutionHokkaido University

Principal Investigator

Haga Hisashi  北海道大学, 先端生命科学研究院, 教授 (00292045)

Co-Investigator(Kenkyū-buntansha) 小林 純子 (仁尾純子)  長崎大学, 高度感染症研究センター, 准教授 (70447043)
Project Period (FY) 2021-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Keywords細胞・組織 / がん細胞 / 集団浸潤 / 細胞間接着構造 / 電子顕微鏡
Outline of Research at the Start

がんは無秩序に無限増殖する細胞の集合体であり,がんが全身に広がることは患者の予後を悪化させる.がんが転移する過程で,がん細胞が周囲の間質中に移動することを浸潤という.培養細胞を用いた浸潤に関する研究の多くは,これまで単一の細胞を対象に行われてきた.しかし,実際の生体内においては,多くのがん細胞種は細胞間の接着を維持したまま集団で浸潤する.このことを集団浸潤という.しかし,その機序については不明な点が多い.そこで本研究は,がん細胞にみられる細胞間接着構造と細胞間に形成される仮足構造を観察・解析するとともに,それらの構成分子およびシグナル経路を明らかにすることで集団浸潤の普遍的機序に迫る.

Outline of Final Research Achievements

Many types of cancer cells invade the stroma collectively while maintaining intercellular adhesion. This phenomenon is referred to as collective invasion. This study aimed to elucidate the mechanism of collective invasion and identify the associated signaling pathways by focusing on the intercellular adhesion structures. In this study, we have shown that collective invasion in human squamous epithelial carcinoma cells (A431 cells) is triggered by the accumulation of Interferon-beta between cells, leading to the activation of STAT1. Furthermore, we discovered that the secreted protein CCL5 induces collective invasion, and an inhibitor of CCR5, the receptor for CCL5, successfully suppresses collective invasion.

Academic Significance and Societal Importance of the Research Achievements

がん細胞に関する研究は,これまで主に単一の細胞を用いて実験が行われてきた.しかし,実際の生体内では,がん細胞はお互いに接着した状態で浸潤することが知られている.そこで,本研究では,Ⅰ型コラーゲンゲルを用いて,がん細胞が集団で浸潤する様子を観察する実験系を構築し,さらに細胞間の接着構造に着目することで,集団浸潤の分子メカニズムに迫った.本研究の成果として,インターフェロンβなど複数のタンパク質が集団浸潤に関わることを明らかにした.これら結果は,将来的にがん細胞の浸潤を抑える創薬研究および治療法の開発へと展開することが期待できる.

Report

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

    (9 results)

All 2024 2023 2022 2021

All Journal Article (5 results) (of which Peer Reviewed: 5 results,  Open Access: 4 results) Presentation (4 results) (of which Int'l Joint Research: 1 results,  Invited: 1 results)

  • [Journal Article] Substrate stiffness induces nuclear localization of myosin regulatory light chain to suppress apoptosis2023

    • Author(s)
      Onishi Katsuya、Ishihara Seiichiro、Takahashi Masayuki、Sakai Akihiro、Enomoto Atsushi、Suzuki Kentaro、Haga Hisashi
    • Journal Title

      FEBS Letters

      Volume: 597 Issue: 5 Pages: 643-656

    • DOI

      10.1002/1873-3468.14592

    • Related Report
      2022 Research-status Report
    • Peer Reviewed
  • [Journal Article] Stiffness-Modulation of Collagen Gels by Genipin-Crosslinking for Cell Culture2023

    • Author(s)
      Ishihara Seiichiro、Kurosawa Haruna、Haga Hisashi
    • Journal Title

      Gels

      Volume: 9 Issue: 2 Pages: 148-148

    • DOI

      10.3390/gels9020148

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The interferon-β/STAT1 axis drives the collective invasion of skin squamous cell carcinoma with sealed intercellular spaces2022

    • Author(s)
      Kumagai Yuji、Nio-Kobayashi Junko、Ishihara Seiichiro、Enomoto Atsushi、Akiyama Masashi、Ichihara Ryosuke、Haga Hisashi
    • Journal Title

      Oncogenesis

      Volume: 11 Issue: 1 Pages: 27-27

    • DOI

      10.1038/s41389-022-00403-9

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Mammaglobin 1 mediates progression of trastuzumab‐resistant breast cancer cells through regulation of cyclins and <scp>NF‐κB</scp>2022

    • Author(s)
      Kusumastuti Ratih、Kumagai Yuji、Ishihara Seiichiro、Enomoto Atsushi、Murakami Takashi、Yasuda Motoaki、Haga Hisashi
    • Journal Title

      FEBS Open Bio

      Volume: 12 Issue: 10 Pages: 1797-1813

    • DOI

      10.1002/2211-5463.13468

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Matrix stiffness contributes to cancer progression by regulating transcription factors2022

    • Author(s)
      Seiichiro Ishihara, Hisashi Haga
    • Journal Title

      Cancers

      Volume: 14 Issue: 4 Pages: 1049-1049

    • DOI

      10.3390/cancers14041049

    • Related Report
      2021 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] Cancer progression regulated by mechanical microenvironment2024

    • Author(s)
      Seiichiro Ishihara, Atsushi Enomoto, Akihiro Sakai, Hisashi Haga
    • Organizer
      International Tumor Microenvironment Seminar in Sapporo
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] I型インターフェロン経路の亢進は扁平上皮がん由来サブクローン細胞の集団浸潤を引き起こす2021

    • Author(s)
      熊谷 祐二, 石原 誠一郎, 芳賀 永
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Research-status Report
  • [Presentation] STAT1活性化は皮膚扁平上皮癌の集団浸潤を促進する2021

    • Author(s)
      熊谷 祐二, 小林 純子, 石原 誠一郎, 芳賀 永
    • Organizer
      第44回日本分子生物学会年会
    • Related Report
      2021 Research-status Report
  • [Presentation] STAT1活性化細胞により誘引される皮膚扁平上皮がんの集団浸潤2021

    • Author(s)
      熊谷 祐二, 小林 純子, 石原 誠一郎, 榎本 篤, 芳賀 永
    • Organizer
      患者由来がんモデル研究会2021
    • Related Report
      2021 Research-status Report

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

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