HIF-2α驱动SCD1介导脂代谢重编程调控TAM/BCSCs细胞间通讯诱导耐药性的分子机制

免疫微环境对乳腺癌耐药根源-乳腺癌干细胞（BCSCs）龛环境保护是制约肿瘤治疗的瓶颈问题。课题组发现HIF-2α调控肿瘤相关巨噬细胞（TAM）M2极化介导BCSCs耐药与诱导脂代谢重编程及CXCL5分泌相关；脂代谢关键酶SCD1启动子存在HIF-2α结合位点；CXCL5通过YAP通路诱导BCCs干性与耐药，因此提出科学假说 “HIF-2α驱动SCD1介导脂代谢重编程调控TAM/BCSCs细胞间通讯诱导BCSCs干性与耐药”，但有待研究证实。本项目将揭示HIF-2α驱动TAM脂代谢重编程介导BCSCs耐药分子机制，明确CXCL5关键媒介作用；通过多学科交叉，探索TAM/BCSCs细胞间通讯促进乳腺癌耐药的具体方式，解析耐药发生新型调控网络与关键环节，明确微环境中驱动肿瘤细胞干性转化和耐药关键因子与分子靶点，研制靶向驱动因子HIF-2α新型抑制剂，为推进肿瘤耐药逆转的个性化治疗提供实验基础。

The niche environment protection of breast cancer stem cells (BCSCs) which leads to drug resistance of breast cancer by the immune microenvironment is a bottleneck that restricts the progress of CSCs targeted therapy. Our previous study found that HIF-2α regulated tumor-associated macrophages (TAM)-M2 polarization to mediate resistance to BCSCs, induced lipid metabolism reprogramming and increased CXCL5 secretion. The promoter of key enzyme of lipid metabolism synthesis, SCD1, contains HIF-2α binding sites. CXCL5 promotes stemness and drug resistance through YAP pathway. The scientific hypothesis that "HIF-2α drives SCD1-mediated lipid metabolism reprogramming to regulate TAM / BCSCs intercellular communication and induces breast cancer resistance" is proposed and further to be elucidated. The study intends to clarify the specific methods of HIF-2α++TAM lipid metabolism reprogramming and promote BCSCs resistance, identify the key mediator role of CXCL5. Our study explores and analyzes the key nodes and pathways of TAM / BCSCs intercellular communication to promote breast cancer resistance through multidisciplinary intersecting, Furthermore, the project identifies key factors and molecular targets which drive stemness transformation and drug resistance of cancer cells, finds new inhibitors targeted to driving-factor HIF-2α, and provides an experimental basis for advancing personalized treatment of cancer drug resistance reversal.