基于微环境介导谷氨酰胺代谢重编程靶点ASCT2的C118P抗三阴乳腺癌转移作用及机制研究

代谢异常是肿瘤的重要特征，也是目前肿瘤研究的新热点。肿瘤微环境作为肿瘤密不可分的功能整体，对其代谢的影响日益受到重视。谷氨酰胺代谢对三阴乳腺癌发展至关重要。作为乳腺最主要的间质—脂肪对乳癌谷氨酰胺代谢的影响还未有报道。本课题拟在既往对乳癌微环境研究基础上，采用体外脂肪细胞与癌细胞共培养模式，体内脂肪与癌细胞共注射模型，探讨脂肪影响三阴乳癌谷氨酰胺代谢关键蛋白ASCT2的原因及机制；利用转录组测序分析ASCT2作用的信号传导通路，探索其调控肿瘤转移的机制；通过反向对接、蛋白共晶及生物学手段，确认ASCT2是C118P抗三阴乳癌转移的靶点。课题将在分子、细胞、整体动物及临床样本水平，从肿瘤代谢异常入手，探讨微环境重塑对乳腺癌转移的影响；基于该理论，从微环境角度研究C118P抗乳腺癌转移作用及机制。研究将为临床三阴乳腺癌治疗提供新的思路和理论依据，对C118P的开发及临床试验具有一定指导意义。

Nowadays, metabolic abnormality is an important feature of tumor and it is also a new hotspot in cancer research. Tumor microenvironment, as an inseparable function of tumor, has been paid more and more attention to its effect on cancer metabolism. Glutamine metabolism is crucial for the development of triple-negative breast cancer (TNBC). Although adipocytes are the main stromal cells in mammary gland, the effect of adipocytes on TNBC glutamine metabolism is unknown. Based on previous study of breast cancer microenvironment, the mechanism and cause of ASCT2 affecting glutamine metabolism in TNBC will be explored by using the co-culture mode of adipocytes with TNBC cells in vitro, and co-injected models of fat with TNBC cells in vivo. In order to explain the mechanism of ASCT2 regulating tumor metastasis, transcriptional gene sequencing will be used to analyze the signal transduction pathway of ASCT2. By reverse docking, protein eutectic and biological methods, we will confirm that ASCT2 will be the target of C118P for anti TNBC metastasis. This study will investigate the effect of microenvironment remodeling on TNBC metastasis in molecular, cellular, animals and clinical samples, which begins with tumor metabolic abnormality. Based on the theory, we will explore the anti-cancer metastasis effect and mechanism of C118P on TNBC in microenvironment. The study will provide a new idea for the treatment of TNBC, and a framework for developing of C118P.