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

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© The Author(s) 2020. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Date Issued
2020-12-07
Publisher Version
10.1038/s41467-020-20054-x
Author(s)
Levi-Galibov, Oshrat
Lavon, Hagar
Wassermann-Dozorets, Rina
Pevsner-Fischer, Meirav
Mayer, Shimrit
Wershof, Esther
Stein, Yaniv
Brown, Lauren E.
Zhang, Wenhan
Friedman, Gil
Nevo, Reinat
Golani, Ofra
Katz, Lior H.
Yaeger, Rona
Laish, Ido
Porco, John A.
Sahai, Erik
Shouval, Dror S.
Kelsen, David
Scherz-Shouval, Ruth
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https://hdl.handle.net/2144/42360
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Published version
Citation (published version)
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, Ruth Scherz-Shouval. 2020. "Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer.." Nat Commun, Volume 11, Issue 1, pp. 6245 - ?. https://doi.org/10.1038/s41467-020-20054-x
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.
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© The Author(s) 2020. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
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