MEF2C介导CAF调节肿瘤血供在胰腺癌中的作用研究

Microvascular density (MVD) is the manifestation of abundance of tumor blood supply. Pancreatic ductal adenocarcinoma (PDAC) has the poorest prognosis among all malignancies, without any efficient treatment. PDAC lacks vessels, and has low MVD; however, the mechanisms have not been well understood. Literatures and our previous work suggested cancer-associated fibroblast (CAF) is a critical factor responsible for decreased MVD in PDAC, and myocyte enhancer factor 2C (MEF2C) is an important regulator of CAF formation. This project will base on our previous work and focus on MVD, using in vitro experiments and conditional knockout mice to study the roles of MEF2C in CAF formation as well as its influence on MVD in PDAC. Furthermore, we will use nanoparticles and a mouse model with spontaneous formed PDAC to explore novel treatment strategy. This project can not only deepen our understanding of the mechanisms by which PDAC does not need abundant blood supply, but also provide experience for novel strategies for PDAC treatment on the basis of MVD reorganization.

微血管密度（microvascular density, MVD）是肿瘤血供丰富程度的体现。胰腺癌血供贫乏，MVD低，预后差，具体机制仍不明了，治疗手段及疗效极其有限。文献报道和我们研究提示：肿瘤相关成纤维细胞（cancer-associated fibroblast, CAF）是胰腺癌MVD降低的关键因素，肌细胞增强因子2（myocyte enhancer factor 2C, MEF2C）是CAF形成的重要调节因子。本课题拟以胰腺癌MVD为切入点，在前期工作基础上，通过体外细胞实验和体内条件性基因敲除小鼠模型，进一步证实MEF2C对胰腺癌CAF形成及其对MVD的影响；借助纳米载体和自发性胰腺癌小鼠模型，探索以MEF2C为靶点干扰CAF形成并调节MVD，从而改善化疗效果的治疗策略。本项目的实施不但可加深对的胰腺癌乏血管机制的理解，还可为探索以重塑MVD为目标的新胰腺癌治疗策略提供借鉴。

肿瘤相关成纤维细胞（Cancer-associated fibroblast, CAF）是胰腺癌中最重要的间质细胞，胰腺星状细胞（Pancreatic stellate cell, PSC）是其主要来源。CAF对肿瘤血供的影响目前报道不一。在本研究中，我们发现了肌细胞增强因子2C（Myocyte enhancer factor 2C, MEF2C）在胰腺癌CAF中高表达，并能调控CAF的活化增殖，同时介导CAF调控肿瘤血管新生及形成。研究表明，MEF2C在人胰腺癌CAF和活化的胰腺星状细胞PSC中高表达，在诱导静息的PSC中表达下调，调控MEF2C表达可以调控PSC的活化状态，使PSC活化形成CAF，也可调节其增殖、迁移和侵袭能力。血管生成能力与CAF表达MEF2C的状态有关，在裸鼠皮下荷瘤模型中CAF表现出对胰腺癌微血管密度的抑制。通过进一步研究证实，MEF2C通过TGF-β1 - MEF2C - TGF-β1正反馈通路介导CAF细胞调控血管新生与生成能力。人胰腺癌中MEF2C表达强化与CAF占比显著相关，并与微血管密度呈负相关趋势，抑制MEF2C能够有效逆转这一过程。此外，我们还发现CAF中MEF2C可通过TGF-β1增加肿瘤相关巨噬细胞TAM上PD-L1的表达，进一步增加TAM的免疫抑制功能。本研究结果不仅有助加深对胰腺癌乏血管机制的理解，还为探索以重塑MVD为目标的胰腺癌治疗新策略提供借鉴，为进一步探索CAF中MEF2C对胰腺癌免疫微环境的影响提供了前期基础。