脑微环境因子共调控SHMT2影响一碳单位代谢促进三阴乳癌脑转移的机制研究

三阴性乳腺癌（TNBC）脑转移发生率高，发生后生存期极短，是目前临床迫切需要解决的难题。本课题组通过临床TNBC患者乳腺原发灶与脑转移灶配对标本的蛋白组/转录组学联合分析，筛选出影响一碳单位代谢的SHMT2是TNBC脑转移发生发展的关键因素，并经本院RNA-seq库和公共数据库佐证。本项目拟在前期工作基础上，进一步分析TNBC脑转移微环境中共调控SHMT2的因子，以Luminal型乳腺癌细胞为对照，通过低氧诱导、星形胶质细胞共培养、microRNA对比筛选等方法，尝试鉴定脑微环境星形胶质细胞与TNBC的互作因子，随后深入探究互作因子、HIF-1α及肿瘤细胞自身Let-7b/SIRT5轴对SHMT2的调控机制。本项目的完成不仅有助于增进对脑微环境因子共调控SHMT2的认识，还能为优化TNBC脑转移预测模型、验证anti-SHMT2抑制TNBC脑转移策略提供可能。

Triple negative breast cancer (TNBC) has a high incidence of brain metastases. Patients with brain metastases are associated with extremely short survival times, which remains the urgent challenge to be solved in clinical practice at present. Gene expression profiling of TNBC patient-matched primary breast tumors and their associated brain metastases was performed by proteomic analysis and transcriptomics analysis. SHMT2 gene, which regulates the amino acid one-carbon unit metabolism, was screened out to be the pivotal gene for brain metastasis. This finding was demonstrated by our RNA-seq database and public databases. Based on our previous work, this project intends to further analyze the factors that co-regulate SHMT2 under the TNBC brain metastasis microenvironment. Taking luminal subtype breast cancer cells as controls, we will perform hypoxia induction, astrocyte co-culture, microRNA comparative screening and other methods to identify the interaction factors between astrocytes and TNBC, and explore the regulation mechanism of SHMT2 by interaction factors, HIF-1α and the tumor cell's own Let-7b/SIRT5 axis. This project will not only help to improve our understanding of the co-regulation of SHMT2 by brain microenvironmental factors, but may also help to develop a brain metastasis risk prediction model and validate the feasibility of anti-SHMT2 as a treatment for TNBC brain metastatic disease.