MEF2C调控CAF促物理/免疫双屏障形成在胰腺癌中的作用及机制研究

Carcinoma-associated fibroblast (CAF) plays a key role in the progression and drug resistance of pancreatic cancer; however, its activation and functions are not fully understood. We first revealed that (1) myocyte enhancer factor 2C (MEF2C) is a critical regulator of CAF formation and functional maintenance, and CAF proliferation causes a physical barrier; (2) MEF2C mediates secretion of tumor growth factor-β (TGF-β), inducing immunosuppressive tumor-associated macrophage (TAM) and forming an immune barrier. The interaction of the two barriers leads to drug resistance of pancreatic cancer, but the underlying mechanism is elusive. In this project, we will use cell models, genetic engineering mouse models, and human tissue samples to figure this issue. We, basing on our previous results, will focus on MEF2C and its role in CAF activation and subsequent TAM induction. By understanding the mechanism of the two-barrier interaction, we hope to develop a novel strategy to reverse drug resistance of pancreatic cancer by targeting MEF2C to destroy the two barriers. This project will not only deepen our understanding of pancreatic tumor microenvironment, but may also shed light on new strategy to treat pancreatic cancer.

肿瘤相关成纤维细胞（CAF）在胰腺癌进展及耐药中发挥重要作用，但其活化和作用机制仍不清。申请人前期研究率先发现：（1）肌细胞增强因子2C（MEF2C）是胰腺癌中调控CAF形成和功能维持的关键因子，CAF增生造成“物理屏障”；（2）MEF2C介导CAF分泌TGF-β，诱导肿瘤相关巨噬细胞（TAM）发挥免疫抑制作用，形成“免疫屏障”。这两层屏障相互作用导致胰腺癌耐药，但具体机制远未明确。本课题拟在前期工作基础上，借助体外细胞实验、基因工程小鼠、人体组织标本等，以MEF2C为切入点，以挖掘CAF与TAM相互作用形成 “物理屏障”和“免疫屏障”效应及其机制为两翼，以探索胰腺癌微环境为主体，以靶向MEF2C破坏物理/免疫双屏障、阻止肿瘤进展和逆转耐药为目标。本项目的实施不仅可以加深对胰腺癌微环境与肿瘤进展、耐药关系及机制的理解，还有望发展出新的干预策略。

尽管目前已有不少研究尝试对胰腺癌微环境中多组分间相互作用进行阐述，尤其是CAF与免疫细胞与肿瘤之间的相互作用，但鲜有研究直接研究CAF功能变化的内源性驱动因素。我们发现MEF2C在胰腺癌中具有独特的表达模式，其在调节CAF活化和功能实现中具有重要作用。我们聚焦于MEF2C调控CAF活化状态与功能变化而引起的一系列微环境组分改变。MEF2C在CAF中的高表达可以促进自身增殖引起的肿瘤纤维化，抑制血管形成引起的乏血供；并且在CAF中MEF2C与TGF-β1相互调控形成正反馈循环后引起TGF-β1主导的免疫抑制。这一系列科学发现或许能为我们带来对胰腺癌全新的认识和治疗创新。