Analysis and functional modulation of the cross-talk between pSTAT3high cancer-associated fibroblasts and tumor cells in colorectal cancer

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Colorectal cancer (CRC) is a frequent disorder and its therapeutic options are still limited. The importance of cancer-associated fibroblasts (CAFs) as a major constituent of the tumor microenvironment (TME) has been increasingly recognized. During the first funding period, we could demonstrate a critical role of pSTAT3 activation in ColVI+ fibroblasts from the tumor microenvironment in a murine model of colon tumors (AOM/DSS). The potential relevance for the human disease was further underlined by the observation that increased stromal STAT3 activation in human colon cancer was associated with reduced overall survival of patients in a cohort of 375 individuals. Subsequent studies are planned taking advantage of the emerging tumor organoid methodology using primary human CRC organoids and corresponding genetically engineered mouse organoids in combination with STAT3-modulated fibroblasts. This research project aims to address the following scientific questions: 1. What are the molecular features on a cellular level of the tumor stroma in CRC with high pSTAT3 in CAFs? 2. How do CAFs and STAT3 activation in CAFs modify the development of primary human tumor organoids and respective genetically engineered mouse organoids in vitro? 3. How do CAFs and STAT3 activation in CAFs modify the growth of primary human tumor organoids and respective genetically engineered mouse organoids in vivo? 4. How do CAFs and STAT3 activation in CAFs modify the cross-talk between lymphocytes and tumor cells in CRC?Our project is intended to analyze the cross-talk between pSTAT3high cancer-associated fibroblasts, lymphocytes and intestinal tumor organoids by modelling the microenvironment of CRC. Thus, this scientific work aims to understand the role of STAT3 in fibroblasts for tumor microenvironment and cancer growth as a basis for the development of novel therapeutic strategies in CRC.