Abstract LB204: HSF1 promotes inflammation induced tumor development through ECM remodeling

Abstract

HSF1 promotes inflammation induced tumor development through ECM remodelingAbstractIn the colon, long-term exposure to chronic inflammation drives colitis associated colon cancer (CAC) in patients with inflammatory bowel disease (IBD). Chronic inflammation underlies tumor initiation, promotion, invasion, and metastasis. While the causal and clinical link between chronic inflammation and CAC is well established, we lack a molecular understanding of what is the way in which chronic inflammation leads to develop colon cancer. Within the tumor, cancer cells are surrounded by a variety of non-malignant cells, such as macrophages, endothelial cells, neutrophils, cancer-associated fibroblasts (CAFs), and together with the extracellular matrix (ECM) they compose the tumor microenvironment (TME), also termed the stroma. Even the most aggressive cancers depend and interact with their environment mostly through secreted factors. Unlike cancer cells, stromal cells are genomically stable, and do not harbor oncogenic mutations that could drive their co-evolution and functional reprogramming. Rather, stromal reprogramming is thought to be achieved by transcriptional rewiring. Previous work by us and others has shown that the master regulator heat shock factor 1 (HSF1) plays a crucial role in this process, by mediating a transcriptional program in fibroblasts that enables their reprogramming into cancer-associated fibroblasts (CAFs) to promote malignancy. We hypothesizde that HSF1 plays a crucial role in inflammation-driven cancer by initiation of a transcriptional program that leads to changes in the extracellular matrix (ECM). We found that, in cell culture, cancer-induced ECM assembly by fibroblasts requires HSF1. Using an inflammation-driven cancer model in mice, we measured the changes in proteomic and ECM organization over time. We found that HSF1 drives a transcriptional program that leads to ECM remodeling in early stages and results in development of colon cancer. Loss of HSF1 prevents inflammation-induced ECM remodeling. Further to that, in CAC patients, we found high activation of stromal HSF1 and similarity to our HSF1 proteomic ECM signature in human colorectal cancer driven by HSF1. Thus, HSF1-dependent ECM remodeling mediates the transition from chronic inflammation to colon cancer. Citation Format: 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. HSF1 promotes inflammation induced tumor development through ECM remodeling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB204.