Revealing biomechanical vulnerabilities in oral cancer cells using 3D coculture platform and low-frequency ultrasound

Achieving selective and efficient targeting of cancer cells while preserving the normal cells remains a crucial obstacle in oral cancer therapies, which compromises patients' quality of life. Here, we present a non-invasive approach using low-frequency ultrasound (US) to exploit the biomechanical vulnerabilities of patient-derived oral cancer cells, thereby promoting selective apoptosis. Cancer cells are subjected to optimized US parameters, revealing selective induction of cancer cell apoptosis (mechanoptosis) without harming normal cells. Reduced expression of the mechanosensory protein Tropomyosin 2.1 (Tpm2.1) in oral cancer cells, due to elevated levels of MicroRNA-21 (miR-21), correlates with heightened sensitivity to US treatment. Furthermore, mechanistic studies demonstrate that US disrupts actomyosin contractility by disassembling myosin IIA fibers, thereby impairing the migration and invasion of cancer cells. Remarkably, a study using an elastomeric platform for coculture of patient-derived cancer and cancer-associated fibroblast (CAF) cells shows a significant reduction in CAFs' ability to infiltrate and compartmentalize the tumor core as well as encapsulate the tumor upon US treatment. Our findings suggest that an ultrasound-based strategy could be used to target the oral tumor microenvironment to augment existing cancer treatment and may open avenues for broader application in superficial malignancies.