Dynamic calcium–potassium balancing by KCNMA1 preserves the epithelial/mesenchymal hybrid state and modulates therapy response in ovarian cancer

Tumor cell plasticity and stemness fuel treatment resistance and cancer evolution into often incurable, metastatic terminal disease. To better understand these fundamental aspects of tumorigenesis, here we examine a potential role of KCNMA1, a calcium-activated potassium channel that impacts cell (patho)physiology through membrane functions, in regulating ovarian cancer cell behavior, including plasticity, proliferation, mobility, and response to treatment. Pharmacological activation of KCNMA1 promoted differentiation, while channel blocking induced dedifferentiation and enhanced dissemination potential. Cyclical activation and inhibition potentiated the epithelial/mesenchymal hybrid cell state prone to stemness. KCNMA1 overexpression combined with low-dose channel blockade supported three-dimensional tumor growth. Mechanistically, we found that the balance between cytosolic calcium and potassium, in addition to their absolute levels, governed the observed changes. Our findings support a model in which KCNMA1-mediated regulation of potassium buffers fluctuating calcium signals that drive phenotypic plasticity, thereby stabilizing the epithelial/mesenchymal hybrid state. In addition, KCNMA1 modulation sensitized ovarian cancer cells to standard-of-care chemotherapeutics. Together, this work provides new insights into the role of KCNMA1 and calcium/potassium homeostasis in ovarian cancer cell adaptability, with implications for treatment.