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

结直肠癌（CRC）是一种常见的疾病，其治疗选择仍然有限。癌症相关成纤维细胞（CAFs）作为肿瘤微环境（TME）的主要组成部分的重要性已经越来越被认识到。在第一个资助期，我们可以在小鼠结肠肿瘤模型（AOM/DSS）的肿瘤微环境中的ColVI+成纤维细胞中证明pSTAT3激活的关键作用。在一项375人的队列研究中，观察到人类结肠癌中基质STAT3激活增加与患者总生存率降低相关，进一步强调了其与人类疾病的潜在相关性。后续的研究计划利用新兴的肿瘤类器官方法，将原发性人CRC类器官和相应的基因工程小鼠类器官与stat3调节的成纤维细胞结合使用。本研究项目旨在解决以下科学问题：1。在结直肠癌中高pSTAT3的肿瘤基质细胞水平上的分子特征是什么？2. 在体外，CAFs和CAFs中STAT3的激活如何改变人类原发肿瘤类器官和相应的基因工程小鼠类器官的发育？3. 在体内，CAFs和STAT3在CAFs中的激活如何改变人类原发肿瘤类器官和相应的基因工程小鼠类器官的生长？4. 在结直肠癌中，CAFs和STAT3的激活如何改变淋巴细胞和肿瘤细胞之间的串扰？我们的项目拟通过模拟结直肠癌的微环境，分析pstat3高癌相关成纤维细胞、淋巴细胞和肠道肿瘤类器官之间的串扰。因此，这项科学工作旨在了解STAT3在成纤维细胞中对肿瘤微环境和癌症生长的作用，作为开发结直肠癌新治疗策略的基础。

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.