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Abstract：
Understanding the cell biological mechanisms that enable tumor cells to persist after therapy is necessary to improve the treatment of recurrent disease. Here, we demonstrate that transient receptor potential channel 6 (TRPC6), a channel that mediates calcium entry, contributes to the properties of breast cancer stem cells, including resistance to chemotherapy, and that tumor cells that persist after therapy are dependent on TRPC6. The mechanism involves the ability of TRPC6 to regulate integrin α6 mRNA splicing. Specifically, TRPC6-mediated calcium entry represses the epithelial splicing factor ESRP1 (epithelial splicing regulatory protein 1), which enables expression of the integrin α6B splice variant. TRPC6 and α6B function in tandem to facilitate stemness and persistence by activating TAZ and, consequently, repressing Myc. Therapeutic inhibition of TRPC6 sensitizes triple-negative breast cancer (TNBC) cells and tumors to chemotherapy by targeting the splicing of α6 integrin mRNA and inducing Myc. These data reveal a Ca2+-dependent mechanism of chemotherapy-induced persistence, which is amenable to therapy, that involves integrin mRNA splicing.
摘要：
了解使肿瘤细胞在治疗后持续存在的细胞生物学机制对于改善复发性疾病的治疗是必要的。这里,我们证明了瞬时受体电位通道6(TRPC6)，介导钙进入的通道，有助于乳腺癌干细胞的特性，包括对化疗的抵抗，治疗后持续存在的肿瘤细胞依赖于TRPC6。该机制涉及TRPC6调节整合素α6mRNA剪接的能力。具体来说,TRPC6介导的钙进入抑制上皮剪接因子ESRP1（上皮剪接调节蛋白1），这使得能够表达整联蛋白α6B剪接变体。TRPC6和α6B串联起作用，通过激活TAZ和促进干性和持久性，因此,压制Myc.TRPC6的治疗性抑制通过靶向α6整合素mRNA的剪接和诱导Myc使三阴性乳腺癌（TNBC）细胞和肿瘤对化疗敏感。这些数据揭示了化疗诱导持续的Ca2+依赖机制，适合治疗，涉及整合素mRNA剪接。
