Ionic regulation of cancer cell stiffness and metastatic colonization via the MRTFA-KCNMB1 axis

Cellular stiffness impacts multiple steps of cancer metastasis, but mechanisms that regulate the stiffness of cancer cells remain poorly understood. Here, we identified potassium efflux and potassium calcium-activated channel subfamily M regulatory beta subunit 1 (KCNMB1), an auxiliary subunit of the large conductance calcium-activated potassium (BK) channels, as regulators of cellular stiffness downstream of myocardin-related transcription factor A (MRTFA). In primary pericytes, KCNMB1 knockdown increased cellular stiffness, which is consistent with the role of potassium efflux in promoting relaxation during excitation-contraction coupling. In a striking contrast, however, KCNMB1 knockdown decreased cancer cells' stiffness. Softer cancer cells were resistant to natural killer (NK) cell mediated cytotoxicity and the low KCNMB1 expression was associated with reduced survival in breast cancer patients. Importantly, pharmacological activation of BK channels reduced metastatic burden in mice and improved lysis of cancer cells by cytotoxic T lymphocytes. These results highlight the ionic regulation of stiffness in cancer cells and point to BK channel agonism as a therapeutic approach.