The calcium channel TRPC6 promotes chemotherapy-induced persistence by regulating integrin α6 mRNA splicing

• Published in: Cell reports (Cambridge) 2023-11, Vol.42 (11), p.113347-113347, Article 113347
• Main Authors: Mukhopadhyay, Dimpi, Goel, Hira Lal, Xiong, Choua, Goel, Shivam, Kumar, Ayush, Li, Rui, Zhu, Lihua Julie, Clark, Jennifer L., Brehm, Michael A., Mercurio, Arthur M.
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents; Calcium - metabolism; Calcium Channels - metabolism; chemoresistance, breast cancer, calcium signaling, mRNA splicing, integrins; CP: Cancer; Integrin alpha6; RNA, Messenger - genetics; RNA, Messenger - metabolism; Transient Receptor Potential Channels; TRPC Cation Channels - genetics; TRPC6 Cation Channel
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2023.113347

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. [Display omitted] •TRPC6 sustains quiescent cancer stem cells in TNBC•TRPC6-mediated Ca2+ maintains stemness by regulating α6 integrin splicing that represses Myc•TNBC cells that persist after chemotherapy are dependent on TRPC6-mediated Myc suppression•Targeted inhibition of TRPC6 sensitizes TNBC to chemotherapy Mukhopadhyay et al. report that TRPC6, a cation channel that mediates calcium entry, distinguishes cancer stem cells from other populations in breast cancer and that it sustains their function. Tumor cells that persist after chemotherapy are dependent on TRPC6, and its targeted inhibition sensitizes them to chemotherapy.