Cell-Type-Specific Mechanical Thresholds of Piezo1 Regulate Cancer Cell Migration and Proliferation

Piezo1 exhibits paradoxical roles in different malignancies, promoting metastasis in some contexts while suppressing tumor progression in others. This functional dichotomy significantly hampers its potential as a therapeutic target. To uncover the mechanistic basis of this phenomenon, we employed correlative atomic force microscopy-confocal laser scanning microscopy (AFM-CLSM) and direct stochastic optical reconstruction microscopy (dSTORM). We found that T24 bladder cancer cells, characterized by high mechanical sensitivity (low threshold), rely on Piezo1-mediated calcium signaling to drive migration via cytoskeletal remodeling and adhesion. In contrast, A549 nonsmall cell lung cancer cells, with low mechanical sensitivity (high threshold), adopt a Piezo1-independent migration mechanism but regulate proliferation through a threshold-sensitive YAP pathway. T24 cells also possess a unique Piezo1-integrin compensatory mechanism that is absent in A549 cells. Based on these findings, we propose a cell-type-specific mechanosensing threshold model in which subthreshold mechanical stimuli activate Piezo1 to promote proliferation, whereas supra-threshold stimulation inhibits growth. This model reveals an adaptive strategy for microenvironmental mechanotransduction in cancer, providing new insights and a theoretical foundation for developing mechanotype-based targeted therapies against Piezo1.