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

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

doi: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.

Highlights

In the colon, long-term exposure to chronic inflammation drives colitis-associated colon cancer (CAC) in patients with inflammatory bowel disease
We find that heat shock factor 1 (HSF1) is activated in stromal fibroblasts during early stages of inflammation, and its activation leads to extracellular matrix (ECM) remodeling, supporting the development of colon cancer
To directly assess the effect of stromal HSF1 on cancer-dependent ECM assembly, we compared the ability of WT and Hsf[1] null mouse embryonic fibroblasts (MEFs) to deposit fibrillar collagen[24], in vitro, in the presence of conditioned media from two different cancer cell-lines, using second harmonic generation (SHG)

Summary

Introduction

Long-term exposure to chronic inflammation drives colitis-associated colon cancer (CAC) in patients with inflammatory bowel disease. HSF1-dependent ECM remodeling plays a crucial role in mediating inflammation-driven colon cancer. A aggressive subtype of CRC is colitis-associated colon cancer (CAC), arising in patients with inflammatory bowel disease (IBD) due to long-term exposure to chronic inflammation[1]. The spectrum of genomic alterations in CAC is distinct from that of sporadic CRC—alterations in TP53, IDH1, and MYC are significantly more frequent in CAC, and mutations in APC are significantly less frequent, than those reported in sporadic CRC2 Both the initiation and the progression of CAC are expedited by the inflammatory insult[4,5].

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Conclusion