Abstract

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.