CLASP1调控DNA同源重组修复在三阴性乳腺癌脑膜转移中的意义及机制研究

三阴性乳腺癌脑膜转移（TNBC LM）是乳腺癌终末期患者致死性并发症之一，缺乏有效的治疗手段，患者临床预后极差。肿瘤耐药是驱动TNBC LM进展的重要原因，然而，导致其耐药的分子机制尚不明确。申请人在前期研究工作中通过分离TNBC LM患者脑脊液肿瘤单细胞并进行转录组测序，并在成功建立TNBC LM小鼠模型的基础上，结合小分子化合物高通量筛选和临床数据分析，发现微管相关蛋白CLASP1在TNBC LM耐药和进展过程中发挥重要作用。基于前期研究结果，申请人提出如下假设：TNBC LM肿瘤细胞在接受化疗药物治疗时发生DNA断裂，CLASP1能够协同RAD51提高肿瘤细胞DNA同源重组修复（HRR）效率，使损伤的DNA得到及时修复，导致TNBC LM肿瘤细胞对化疗药物的敏感性降低，耐药的肿瘤细胞再次定植、生长，引起病灶播散。本申请课题拟验证上述研究假设，为TNBC LM的临床诊治提供理论依据。

Leptomeningeal metastases in triple-negative breast cancer (TNBC LM) patients are rare but often accompanied by devastating neurological symptoms and carry a very poor prognosis, even if treated. However, the molecular drive mechanism of TNBC LM is largely unknown. In our previous work, we characterized a human-in-mouse TNBC LM model, recapitulating the stages, heterogeneity, and spatial distribution of human TNBC LM. We performed the single cell RNA-sequencing, high-throughput drug screening and clinical data analysis, and found that CLASP1, known for its role in endocytic cell trafficking and microtubule dynamics, plays an important role in TNBC LM chemotherapy resistance. Taken together, we reasoned that if CLASP1 levels, synergizing with RDA51, were important in enabling homologous recombination repair (HRR), which then potentially could predict the response to therapy of patients with TNBC LM.