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

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, Ofra Golani, Lior H. Katz, Rona Yaeger, Ido Laish, John A. Porco, Erik Sahai, Dror S. Shouval, David Kelsen and Ruth Scherz-Shouval ()
Additional contact information
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
Rona Yaeger: Memorial Sloan Kettering Cancer Center, and Weil Cornell Medical College
Ido Laish: Sheba Medical Center, Tel Hashomer
John A. Porco: Boston University
Erik Sahai: The Francis Crick Institute
Dror S. Shouval: Tel-Aviv University
David Kelsen: Memorial Sloan Kettering Cancer Center, and Weil Cornell Medical College
Ruth Scherz-Shouval: The Weizmann Institute of Science

Nature Communications, 2020, vol. 11, issue 1, 1-19

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-20054-x

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