Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancerMore about Open Access at the Crick
Authors listOshrat 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 Ruth Scherz-Shouval
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.
Journal Nature Communications
Issue number 1