Irregular Curvature at Focal Adhesions Modulates Piezo1 Activity and Low Frequency Ultrasound Induced Apoptosis in Cancer Cells

Low-frequency, low intensity ultrasound (LIUS) has emerged as a promising physical modality capable of inducing selective apoptosis of cancer cells, while sparing healthy epithelial cells and fibroblasts. Hitherto, the mechanism underlying this selectivity has been unclear, but we now propose and develop a theoretical framework linking the distinct mechanical behaviours of cancer versus healthy cells to their differential responses to LIUS. We point out that cancer cells exhibit inhomogeneous ventral stress-fiber networks, which can produce irregular focal adhesion geometry and inward membrane curvature near focal adhesions under low-intensity ultrasound (LIUS). These curvature irregularities can favor loose packing of Piezo1 channels, thereby preserving their activity. In contrast, healthy epithelial cells and fibroblasts display more homogeneous cytoskeletal organization, which can result in more regular curvature profiles adjacent to focal adhesions. This leads to curvature-driven cholesterol redistribution, resulting in altered spatial organization of Piezo1 clusters and reduced coordinated channel activity and allowing cells to remain in their active, proliferative state when exposed to LIUS. Based on theoretical modeling and previous experimental findings, we propose that differences in cytoskeletal organization and membrane curvature can contribute to distinct Piezo1 activation patterns between healthy and cancerous cells. Our analysis identifies curvature-mediated Piezo1 redistribution as a potential physical basis for LIUS selectivity and provides a mechanistic foundation for designing ultrasound-based therapies to exploit the intrinsic cytoskeletal vulnerabilities of cancer cells.