YAP在细胞外基质拓扑结构对树突状细胞功能影响中的作用和机制研究

Dendritic cells (DCs) are the most powerful antigen presenting cells, which play a crucial role in the initiation of immune responses against cancer. The phenotype and antigen presentation capacity of DCs can be affected by the abnormal biomechanical microenvironment that caused by the remodeling of tumor extracellular matrix (ECM), but the underlying mechanisms are not well defined. Yes-associated protein (YAP) is the primary participant in the Hippo-YAP signaling pathway. YAP can function as a mechanosensor which play a vital role in cell response to the mechanical force. Our previous results showed that DCs can respond to ECM with different dimensions, and the expression patterns of YAP in imDCs and mDCs are different. Therefore, the extracellular biomechanical environment with different patterns will be constructed to simulate the topological changes of tumor microenvironment. Then, the phenotype, biomechanical properties and immune function of DCs in different matrix mechanical environments will be investigated. Simultaneously, the roles and mechanisms of Yap in the response of DCs against ECM topology will be elaborated. It is of great significance to further understand the DC dyfunction in tumor microenvironment and its molecular mechanisms.

树突状细胞（dendritic cells, DCs）作为目前已知机体内功能最为强大的抗原提呈细胞，在肿瘤免疫应答的启动过程中起着关键作用。肿瘤细胞外基质重塑引起的异常的力学环境会影响DCs的表型和抗原提呈能力，但潜在机制并不完全清楚。Yes相关蛋白（Yes-associated protein, YAP）是Hippo-YAP信号通路的主要参与者，是外界力学信号的接收器，在细胞对力学力的应答过程中发挥至关重要的作用。课题组前期研究发现，DCs能够对具有不同维度的细胞外基质环境做出应答，且imDCs和mDCs内YAP的表达方式不同。因此，本项目将通过构建不同拓扑细胞外基质力学环境来模拟肿瘤微环境拓扑结构的改变，研究其对DCs的细胞形态、生物力学特性及免疫学功能的影响，并分析YAP在此过程中的作用及其分子机制，这对深入理解肿瘤微环境下DCs功能的抑制及作用机理具有重要的意义。

树突状细胞（dendritic cells, DCs）作为目前已知机体内功能最为强大的抗原提呈细胞，在肿瘤免疫应答的启动过程中起着关键作用。肿瘤细胞外基质重塑引起的异常的力学环境会影响DCs的表型和抗原提呈能力，但潜在机制并不完全清楚。课题组前期研究发现，DCs能够对具有不同维度的细胞外基质环境做出应答。本项目制备了无孔径及具有类圆形孔径的基底模拟不同拓扑结构的细胞外基质环境，探索不同拓扑结构对DCs细胞骨架结构、迁移能力和免疫学功能的影响，并分析了潜在的分子机制。研究结果表明，DCs细胞骨架F-actin能够对不同拓扑结构做出应答并发生重塑，细胞形态发生了明显变化；不同拓扑结构能够影响DCs的迁移能力；DCs的免疫功能受细胞外基质拓扑结构的调控；DCs在不同拓扑结构上的mRNA表达谱不同，涉及的分子机制包含丝裂原活化蛋白激酶（mitogen-activated protein kinase, MAPK）信号通路、趋化因子信号通路、白细胞介素17(interleukin 17, IL-17)信号通路和Toll样受体信号通路等。同时，不同生长方式的细胞中Yes相关蛋白（Yes-associated protein, YAP）的表达具有差异。以上结果对进一步深入理解细胞外基质拓扑结构对DCs免疫功能的调控奠定了基础，也为DCs的临床应用提供了理论依据。