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。在这里，我们证明瞬时受体电位通道 6 (TRPC6)（一种介导钙进入的通道）有助于乳腺癌干细胞的特性，包括对化疗的抵抗力，并且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 α6 mRNA 剪接的能力。具体来说，TRPC6 介导的钙内流会抑制上皮剪接因子 ESRP1（上皮剪接调节蛋白 1），从而使整合素 α6B 剪接变体得以表达。 TRPC6 和 α6B 协同作用，通过激活 TAZ 并因此抑制 Myc 来促进干性和持久性。 TRPC6 的治疗性抑制通过靶向 α6 整合素 mRNA 的剪接并诱导 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引起的持久性的 Ca2 依赖性机制，该机制适合治疗，涉及整合素 mRNA 剪接。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

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.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.