Journal
NATURE COMMUNICATIONS
Volume 11, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s41467-020-20054-x
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Funding
- NIH [R35GM118173, U01TR002625]
- Crohn's and Colitis Foundation
- Liane Ginsberg Foundation
- STARR Cancer Consortium Grant
- NCI Core Grant [P30 CA008748]
- Francis Crick Institute from Cancer Research UK [FC010144]
- UK Medical Research Council [FC0010144]
- Wellcome Trust [FC010144]
- Israel Science Foundation [401/17, 1384/1]
- European Research Council (ERC) [754320]
- Minerva foundation
- Israel cancer research fund
- Laura Gurwin Flug Family Fund
- Peter and Patricia Gruber Awards
- Comisaroff Family Trust
- Estate of Annice Anzelewitz
- Estate of Mordecai M. Roshwal
- European Research Council (ERC) [754320] Funding Source: European Research Council (ERC)
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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. Expression and activation of Heat shock factor 1 (HSF1) in cancer associated fibroblasts have been associated with protumorigenic functions. Here the authors show that, in a model of colitis-induced colorectal cancer, HSF1 is activated in stromal fibroblasts in the early stages of inflammation, leading to extracellular matrix remodelling that sustains tumor initiation and progression.
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