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

结直肠癌（CRC）是一种常见疾病，其治疗选择仍然有限。癌症相关成纤维细胞（CAF）作为肿瘤微环境（TME）的主要组成部分的重要性已越来越被认识到。在第一个资助期间，我们可以证明pSTAT 3激活在结肠肿瘤小鼠模型（AOM/DSS）中来自肿瘤微环境的ColVI+成纤维细胞中的关键作用。通过观察到人结肠癌中增加的基质STAT 3活化与375个个体的队列中患者的总存活率降低相关，进一步强调了与人类疾病的潜在相关性。后续研究计划利用新兴的肿瘤类器官方法，使用原代人CRC类器官和相应的基因工程小鼠类器官与STAT 3调节的成纤维细胞组合。本研究项目旨在解决以下科学问题：1。在CAFs中pSTAT 3高表达的CRC肿瘤间质细胞水平上的分子特征是什么？ 2. CAF和CAF中的STAT 3激活如何在体外改变原发性人类肿瘤类器官和相应的基因工程小鼠类器官的发育？3. CAF和CAF中的STAT 3激活如何改变体内原发性人类肿瘤类器官和相应的基因工程小鼠类器官的生长？4. CAF和CAF中的STAT 3激活如何改变CRC中淋巴细胞和肿瘤细胞之间的相互作用？我们的项目旨在通过模拟CRC的微环境来分析pSTAT 3 high癌症相关成纤维细胞，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STAT 3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CRC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.