基质硬度引起的肿瘤相关巨噬细胞脂代谢重塑促进胃癌生长的机制研究

细胞外基质的硬度在肿瘤恶性进程中的作用渐受重视。然而，尚无研究涉及基质硬度对肿瘤相关巨噬细胞（TAMs）表型与代谢模式的影响。另外，TAMs的脂代谢对其发挥生物学功能的作用亦有待阐明。通过文献检索与前期预实验结果，我们推测基质硬度的增加可促使TAMs表型向免疫抑制型激活，并增强其脂解代谢与磷脂代谢，促进游离脂肪酸与前列腺素PGE2的释放。而TAMs的脂代谢重塑既有助于其免疫抑制表型的激活与维持，也影响着TAMs对胃癌细胞生物学行为的调控。因此，本项目旨在探讨基质硬度引起的TAMs脂代谢重塑促进胃癌生长的机制，通过体外制备不同硬度的聚丙烯酰胺水凝胶基底模拟细胞外基质，观察不同梯度基质硬度对TAMs的表型、代谢模式及其促胃癌生长作用的影响，阐明具体的信号通路，并在动物模型中予以验证，以期从力学微环境与细胞代谢角度为TAMs促癌的机制提供新的分子生物学依据与潜在的治疗靶点。

The extracellular matrix stiffness has been attracting attention for its role in tumor progression. However, the effects of matrix stiffness on tumor-associated macrophages (TAMs) phenotype activation and metabolic adaptation still remain unclear. In addition, how the lipid metabolism of TAMs affects its biological function has yet to be elucidated. Through literature review and preliminary experimental results, we infer that higher matrix stiffness may elicit the immunosuppressive form of TAMs activation, enhance the lipolysis and phospholipid metabolism, as well as promote release of free fatty acid and prostaglandin E2. The lipid metabolism orchestration of TAMs not only contributes to the activation and maintenance of its immunosuppressive phenotype, but also affects the regulation of TAMs on the biological behavior of gastric cancer cells. This project aims to clarify the molecular mechanism under TAMs promoting gastric cancer growth via their lipid metabolism reprogramming caused by matrix stiffness, through in vitro production of polyacrylamide hydrogel substrates to model the extracellular matrix, as well as by conducting cell function experiments, molecular biological experiments and constructing animal models. Finally, this project would provide a brand new molecular basis for the tumor promoting role of TAMs in terms of mechanical environment and cellular energy metabolism.