CD146-Integrin β1共受体激活LATS1-YAP信号轴促进乳腺癌细胞逃逸放疗DNA损伤的分子机制及其临床意义研究

放疗是乳腺癌重要的局部治疗手段，而肿瘤固有或获得性辐射抵抗降低了放疗疗效，是治疗难点。本项目前期细胞系和裸鼠成瘤实验发现，CD146是促进乳腺癌细胞放疗抵抗的重要膜受体；初步机制探索发现，CD146促进DNA损伤修复反应，并通过调控LATS1激活YAP蛋白及其核转移；经CO-IP与蛋白质谱鉴定，CD146可与整合素Integrin β1相互作用且在接受放疗后更显著，提示两者的互作可能是放疗抵抗的关键节点。因此，我们提出假说：CD146与Integrin β1形成共受体，通过招募关键互作蛋白介导LATS1-YAP信号轴，最终导致乳腺癌细胞放疗抵抗。本项目拟在乳腺癌细胞系、裸鼠成瘤、类器官3D培养等模型和临床组织水平，系统阐明CD146如何介导信号跨膜以及胞内传递，厘清该信号通路失调与放疗抵抗的相关分子机制。该研究成果将为放疗抵抗型乳腺癌的靶向药物开发以及临床转化应用提供有价值的科学依据。

Radiotherapy (RT) plays a pivotal role in the standard regional therapy for breast cancer, however, intrinsic or acquired resistance to radiotherapy, a barrier to yield clinical benefit, can be one of the main reasons of local recurrence or even leading to distant metastasis. Our previous work found that CD146, a transmembrane receptor protein, implicated in the acquisition of radio-resistance. Further investigation found that CD146 promotes DNA damage repair response and activates YAP activity (nuclear translocation) by regulating LATS1. Moreover, CD146 is found to be interacted with integrin β1 by Co-IP and mass spectrometry, especially when cells exposed to radiation. These results suggest that CD146- integrin β1 interaction maybe a core step in activating downstream signaling networks associated with radio-resistance. Therefore, we hypothesize that CD146, a potential coreceptor of integrin β1, is capable of recruiting key effectors to activate LATS1-YAP signaling and induce radiation-resistance in breast cancer. In this project, we intend to investigate the underlying mechanism of CD146 receptor signaling transduction in contribution to radio-resistance through experiments in cell lines, tumor xenograft- and organoid-models, as well as human breast cancer tissues. This study would be instrumental in developing novel targeted drugs for radio-resistant breast cancer.