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; Ruth Scherz-Shouval

doi:10.1038/s41467-020-20054-x

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, Ruth Scherz-Shouval

Weizmann Institute of Science, Tel Aviv University

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	6245
Number of pages	19
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20054-x
State	Published - 7 Dec 2020

All Science Journal Classification (ASJC) codes

General Chemistry
General Biochemistry,Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Levi-Galibov, O., Lavon, H., Wassermann-Dozorets, R., Pevsner-Fischer, M., Mayer, S., Wershof, E., Stein, Y., Brown, L. E., Zhang, W., Friedman, G., Nevo, R., Golani, O., Katz, L. H., Yaeger, R., Laish, I., Porco, J. A., Sahai, E., Shouval, D. S., Kelsen, D., & Scherz-Shouval, R. (2020). Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer. Nature Communications, 11(1), Article 6245. https://doi.org/10.1038/s41467-020-20054-x

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

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.",

author = "Oshrat Levi-Galibov and Hagar Lavon and Rina Wassermann-Dozorets and Meirav Pevsner-Fischer and Shimrit Mayer and Esther Wershof and Yaniv Stein and Brown, {Lauren E.} and Wenhan Zhang and Gil Friedman and Reinat Nevo and Ofra Golani and Katz, {Lior H.} and Rona Yaeger and Ido Laish and Porco, {John A.} and Erik Sahai and Shouval, {Dror S.} and David Kelsen and Ruth Scherz-Shouval",

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doi = "10.1038/s41467-020-20054-x",

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Levi-Galibov, O, Lavon, H, Wassermann-Dozorets, R, Pevsner-Fischer, M, Mayer, S, Wershof, E, Stein, Y, Brown, LE, Zhang, W, Friedman, G, Nevo, R, Golani, O, Katz, LH, Yaeger, R, Laish, I, Porco, JA, Sahai, E, Shouval, DS, Kelsen, D & Scherz-Shouval, R 2020, 'Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer', Nature Communications, vol. 11, no. 1, 6245. https://doi.org/10.1038/s41467-020-20054-x

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T1 - Heat Shock Factor 1-dependent extracellular matrix remodeling mediates the transition from chronic intestinal inflammation to colon cancer

AU - Levi-Galibov, Oshrat

AU - Lavon, Hagar

AU - Wassermann-Dozorets, Rina

AU - Pevsner-Fischer, Meirav

AU - Mayer, Shimrit

AU - Wershof, Esther

AU - Stein, Yaniv

AU - Brown, Lauren E.

AU - Zhang, Wenhan

AU - Friedman, Gil

AU - Nevo, Reinat

AU - Golani, Ofra

AU - Katz, Lior H.

AU - Yaeger, Rona

AU - Laish, Ido

AU - Porco, John A.

AU - Sahai, Erik

AU - Shouval, Dror S.

AU - Kelsen, David

AU - Scherz-Shouval, Ruth

PY - 2020/12/7

Y1 - 2020/12/7

N2 - 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.

AB - 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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U2 - 10.1038/s41467-020-20054-x

DO - 10.1038/s41467-020-20054-x

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SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6245

ER -

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

Abstract

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