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

ABSTRACT: Chronic inflammation underlies tumor initiation, progression, invasion, and metastasis. In the colon, long-term exposure to chronic inflammation drives colitis associated colon cancer (CAC) in patients with inflammatory bowel disease (IBD). While the causal and clinical links between chronic inflammation and CAC are well established, our molecular understanding of how chronic inflammation leads to the development of colon cancer is still lacking. Here we deconstruct the evolving microenvironment of CAC, by measuring proteomic changes and extracellular matrix (ECM) organization over time in a genetically modified mouse model of CAC. We detect early changes in ECM structure and composition, and report that the transcriptional regulator heat shock factor 1 (HSF1) plays a crucial role in orchestrating these events. Activated in stromal fibroblasts of the gut, HSF1 promotes ECM remodeling and inflammatory programs which lead to the development of CAC. Loss of HSF1 abrogates ECM assembly by colon fibroblasts in cell culture, prevents inflammation-induced ECM remodeling in mice and significantly inhibits progression to CAC. Establishing the relevance of our experimental findings 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE158276 | GEO | 2020/11/05

REPOSITORIES: GEO

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Project description:The molecular basis of breast cancer invasion and metastasis is not well understood. Our objective was to analyze transcriptome differences between stromal and epithelial cells in normal breast tissue and invasive breast cancer to define the role stroma plays in invasion. Total RNA was isolated from epithelial and stromal cells that were laser captured from normal breast tissue (n=5) and invasive breast cancer (n=28). Gene expression was measured using Affymetrix U133A 2.0 GeneChips. Differential gene expression was evaluated and compared within a model that accounted for cell type (epithelial [E] versus stromal [S]), diagnosis (cancer [C] versus normal [N]) as well as cell type-diagnosis interactions. Compared to NE, the CE transcriptome was highly enriched with genes in proliferative, motility and ECM ontologies. Differences in CS and NS transcriptomes suggested that the ECM was being remodeled in invasive breast cancer, as genes were over-represented in ECM and proteolysis ontologies. Genes more highly expressed in CS compared to CE were primarily ECM components or were involved in the remodeling of ECM, suggesting that ECM biosynthesis and remodeling were initiated in the tumor stromal compartment. Experiment Overall Design: Breast tissue was collected at surgery from patients undergoing surgical resection for invasive breast cancer (n=28) and reduction mammoplasty (n=5). Tissue was cryopreserved in OCT and serial sections were cut using a cryostat. Sections were stained and epithelial and stromal cells were isolated by laser capture microdissection. Total RNA was isolated and target was prepared using NuGen Ribo-SPIA Ovation Technology. Gene expression was measured using Affymetrix U133A 2.0 GeneChips. Gene expression differences were evaluated using a linear model of the Robust Multichip Average gene expression statistic, a model that accounted for cell type (E and S), patient diagnosis (C and N), as well as cell type-diagnosis interactions. Data were examined to determine false discovery rate and were filtered for fold changes in gene expression and p-value.

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

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