乳腺癌上皮间质转化中核苷酸代谢相关的功能蛋白发现和机理研究

上皮间质转化EMT与乳腺癌的浸润转移、耐药性发生有密切联系。EMT发生分子机制非常复杂，仍需要进一步的探究和阐明，需要新的研究角度和手段。我们前期利用新近开发的CETSA-IMPRINTS方法，得到了乳腺癌EMT过程中组学水平上的“在体”蛋白质的动态调节信息，并从中发现了包括胸苷酸合成酶TYMS和琥珀酰辅酶A合成酶SCS在内的若干个参与核苷酸代谢蛋白很可能在间质表型细胞中处于（加强）活化状态。考虑到越来越多的证据表明细胞代谢重编程与EMT的发生密切相关，靶向癌细胞的代谢途径将有可能成为逆转EMT从而控制癌症转移的新途径。本课题拟围绕这两个核苷酸代谢蛋白进行细致深入的细胞功能验证和生化分析，明确它们与EMT发生的相关性，理解其具体的分子作用机制，为乳腺癌EMT相关的代谢重编程机制研究提供理论和实验依据，最终为乳腺癌的治疗和干预提供潜在的新型功能蛋白靶点。

Epithelial-mesenchymal transition is closely related to the invasion, metastasis and the development of drug resistance in breast cancer. The underlying mechanisms of EMT activation are very complex and remain to be further studied and explored, probably with new research perspectives and tools. Recently we have applied the newly-developed CETSA-IMPRINTS methodology and got the proteome-wide information of the changes of “in situ” protein level and protein interaction states during the transition. Among these proteins with dynamic regulation, we found that two enzyme proteins––Thymidylate synthase (TYMS) and Succinate-CoA synthetase (SCS)––in the nucleotide metabolism pathway, are probably in the (enhanced-) activation state. Considering the accumulating evidence on the close relationship of metabolic reprogramming and the activation of EMT, it suggests that targeting the metabolic pathways of cancer cells could be a potential route for reversing EMT and controlling of metastasis in cancer therapy. In this proposal, we plan to carry out detailed functional characterizations and biochemical analyses on these two proteins, aim to confirm their roles in the activation of EMT and understand the underlying molecular mechanisms of action, thereby providing theoretical and experimental evidence for the metabolic reprogramming of breast cancer cells in EMT, eventually providing new potential functional targets for breast cancer therapy and intervention.