GSE158276
Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer
Chronic inflammation underlies tumor initiation, progression, invasion, and metastasis. In the colon, long-term exposure to chronic inflammation drives colitis associated colon cancer (CAC) in patients with inflammatory bowel disease (IBD). While the causal and clinical links between chronic inflammation and CAC are well established, our molecular understanding of how chronic inflammation leads to the development of colon cancer is still lacking. Here we deconstruct the evolving microenvironment of CAC, by measuring proteomic changes and extracellular matrix (ECM) organization over time in a genetically modified mouse model of CAC. We detect early changes in ECM structure and composition, and report that the transcriptional regulator heat shock factor 1 (HSF1) plays a crucial role in orchestrating these events. Activated in stromal fibroblasts of the gut, HSF1 promotes ECM remodeling and inflammatory programs which lead to the development of CAC. Loss of HSF1 abrogates ECM assembly by colon fibroblasts in cell culture, prevents inflammation-induced ECM remodeling in mice and significantly inhibits progression to CAC. Establishing the relevance of our experimental findings 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. Overall design: Bulk RNA expression of 8 samples, in duplicate for each condition, from 9.5 week old HSF1-null and HSF1 WT mice treated and not treated(Control) with one cycle of AOM-DSS