12HETE/GPR31通路介导癌相关成纤维细胞重编程参与乳腺癌转移的机制研究

如何控制肿瘤的复发和转移，是乳腺癌治疗上亟待解决的问题。肿瘤微环境，特别是近年发现的癌相关成纤维细胞在肿瘤转移过程中发挥了重要作用，但其机制仍不清楚。脂代谢重新编程产物12-HETE及其受体GPR31发挥了多层次促癌作用，但其在乳腺癌相关成纤维细胞中的作用仍然未知。根据前期研究结果，我们发现12HETE/GPR31在乳腺癌组织及癌相关成纤维细胞中的表达明显升高，且其细胞伴侣介导的自噬相关蛋白及趋化因子CCL2,CCL5水平明显升高，提示12HETE/GPR31通路能通过调控分子伴侣介导的自噬，参与癌相关成纤维细胞的糖酵解重编程和促炎因子释放等，从而参与肿瘤的转移。因此，本课题组以肿瘤代谢重编程产物为切入点，系统解析12-HETE/GPR31通路介导癌相关成纤维细胞调控乳腺癌转移作用和具体机制，从脂代谢重编程的角度为针对乳腺癌提供新的治疗策略和理论基础。

Identication of novel druggable metastasis activators will be fundamentally important for cancer prevention and treatment. Microenviroment, especially thecancer-associated fibroblast (CAF) was believed to play a vital role in the disease progression and relapse, although the underlying mechanisms remain unclear. 12-HETE, a lipid metabolic reprogramming product, and its receptor GPR31 were found to play an important role in tumor initiation and progression. However, the effect of 12HETE/GPR31 pathway in the CAF is yet unknown. In our preliminary experiments, 12-HETE is higher in both tumor tissue samples and CAFs. Moreover, the markers of chaperone-mediated autophagy (CMA) as well as chemokines (CCL2,CCL5) were also up-regulated. These result taken together strongly suggest that the 12HETE-GPR31 modulated CMA, contributed to the tumor progression and relapse through regulation the metabolic reprogramming and inflammatory factors release. Therefore, taken the metabolic reprogramming as a cutpoint, we sought to evaluate the functional role and the underlying mechanisms of 12HETE/GPR31 pathway in the CAF-mediated tumor metastasis, and thus provide novel venues and evidence for CAF-targeted strategies against metabolic reprogramming related pathway.