基于胃癌临床队列的多组学分子网络谱图绘制及关键治疗靶点的机制探索

前期我们从基因组，转录组，蛋白组等多维度系统探索胃癌预后和耐药的分子亚型，筛选和验证了一系列影响化疗疗效和转移预后的标志物，但缺乏肿瘤微生态的整体视角。本项目将在前期基础上，对胃癌中肿瘤细胞的基因变异、代谢重编程与肿瘤微环境之间的分子网络交互作用在胃癌耐药和转移中的发展特征进行深入探索。一方面按照新辅助化疗疗效建立差异队列，对化疗前后患者肠道微生物菌群和代谢物进行比较动态比较，明确其与化疗耐药之间的相关性，探索可能的耐药菌群及其调控代谢的分子机制，寻找治疗靶点。另一方面按照术后复发转移建立临床预后差异队列，进行非靶向蛋白组学和非靶向代谢组学联合研究，探明胃癌细胞代谢对肿瘤本身和微环境之间的动态调节及其对转移和预后的影响，寻找其中作用的关键分子深入分析其作用机理。最终揭示肿瘤分子变异、微环境诱导、能量代谢改变之间交互作用与胃癌进展的因果关联，打开新的治疗思路。

Previous study have systematically explored the molecular subtypes of gastric cancer progressin and drug resistance from multiple dimensions including genomic, transcriptomic, and proteomic analysis, then screened and verified a series of molecular markers that may predict the efficacy of chemotherapy and the prognosis of gastric cancer. In this project, we will explore in depth the developmental characteristics of the molecular network interaction between tumor cell genetic variation, metabolic reprogramming and tumor microenvironment in drug resistance and metastasis of gastric cancer . On the one hand, according to the efficacy of neoadjuvant chemotherapy, a differential cohort would be established to compare the dynamics of patients' intestinal microflora and metabolites before and after chemotherapy, to clarify their correlation with chemotherapy resistance, and to explore possible drug-resistant flora and their regulation Molecular mechanism of metabolism, looking for therapeutic targets. On the other hand, according to the postoperative recurrence and metastasis, the prognostic diffrentiated cohort would be established. A joint study of non-targeted proteomics and non-targeted metabolomics was conducted to analyze possible metabolic abnormalities, and further investigate the metabolism regulation between microenvironments and tumor cells and finally affects prognosis, looking for the key molecules and analyze its mechanism of action. Finally, it reveals the causal relationship between tumor molecular variation, microenvironment induction, and energy metabolism changes and gastric cancer progression.