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Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer

Author

Listed:
  • Oshrat Levi-Galibov

    (The Weizmann Institute of Science)

  • Hagar Lavon

    (The Weizmann Institute of Science)

  • Rina Wassermann-Dozorets

    (The Weizmann Institute of Science)

  • Meirav Pevsner-Fischer

    (The Weizmann Institute of Science)

  • Shimrit Mayer

    (The Weizmann Institute of Science)

  • Esther Wershof

    (The Francis Crick Institute)

  • Yaniv Stein

    (The Weizmann Institute of Science)

  • Lauren E. Brown

    (Boston University)

  • Wenhan Zhang

    (Boston University)

  • Gil Friedman

    (The Weizmann Institute of Science)

  • Reinat Nevo

    (The Weizmann Institute of Science)

  • Ofra Golani

    (The Weizmann Institute of Science)

  • Lior H. Katz

    (Sheba Medical Center, Tel Hashomer
    Hadassah Medical Center)

  • Rona Yaeger

    (Memorial Sloan Kettering Cancer Center, and Weil Cornell Medical College)

  • Ido Laish

    (Sheba Medical Center, Tel Hashomer
    Tel-Aviv University)

  • John A. Porco

    (Boston University)

  • Erik Sahai

    (The Francis Crick Institute)

  • Dror S. Shouval

    (Tel-Aviv University
    Sheba Medical Center)

  • David Kelsen

    (Memorial Sloan Kettering Cancer Center, and Weil Cornell Medical College)

  • Ruth Scherz-Shouval

    (The Weizmann Institute of Science)

Abstract

In the colon, long-term exposure to chronic inflammation drives colitis-associated colon cancer (CAC) in patients with inflammatory bowel disease. While the causal and clinical links are well established, molecular understanding of how chronic inflammation leads to the development of colon cancer is lacking. Here we deconstruct the evolving microenvironment of CAC by measuring proteomic changes and extracellular matrix (ECM) organization over time in a mouse model of CAC. We detect early changes in ECM structure and composition, and report a crucial role for the transcriptional regulator heat shock factor 1 (HSF1) in orchestrating these events. Loss of HSF1 abrogates ECM assembly by colon fibroblasts in cell-culture, prevents inflammation-induced ECM remodeling in mice and inhibits progression to CAC. Establishing relevance to human disease, we find high activation of stromal HSF1 in CAC patients, and detect the HSF1-dependent proteomic ECM signature in human colorectal cancer. Thus, HSF1-dependent ECM remodeling plays a crucial role in mediating inflammation-driven colon cancer.

Suggested Citation

  • Oshrat Levi-Galibov & Hagar Lavon & Rina Wassermann-Dozorets & Meirav Pevsner-Fischer & Shimrit Mayer & Esther Wershof & Yaniv Stein & Lauren E. Brown & Wenhan Zhang & Gil Friedman & Reinat Nevo & Ofr, 2020. "Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer," Nature Communications, Nature, vol. 11(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:11:y:2020:i:1:d:10.1038_s41467-020-20054-x
    DOI: 10.1038/s41467-020-20054-x
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    Cited by:

    1. Lee Shaashua & Aviad Ben-Shmuel & Meirav Pevsner-Fischer & Gil Friedman & Oshrat Levi-Galibov & Subhiksha Nandakumar & Debra Barki & Reinat Nevo & Lauren E. Brown & Wenhan Zhang & Yaniv Stein & Chen L, 2022. "BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking clusterin expression in cancer associated fibroblasts with HSF1 signaling," Nature Communications, Nature, vol. 13(1), pages 1-21, December.

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