Restoring the tumour mechanophenotype of vocal fold cancer reverts its malignant properties.

Increased extracellular matrix deposition and stiffness promotes solid tumour progression. Yet, the precise mechanotransduction pathways, especially in less-studied mechanically responsive cancers, remain poorly understood. Here we address this gap using patient-derived tumour cells from early (mobile, T1) and advanced (immobile, T3) stages of vocal fold cancer, the most common squamous cell carcinoma severely impacting the voice box. We reveal that vocal fold cancer progression is linked to cell surface receptor heterogeneity, a loss of laminin-binding integrins in cell-cell junctions and a flocking mode of collective cell motility. Mimicking the physiological movement of healthy vocal fold tissue with stretching or vibrations decreases oncogenic β-catenin and Yes-associated protein (YAP) nuclear levels in vocal fold cancer. Multiplex immunohistochemistry of vocal fold cancer tumours shows a correlation between the extracellular matrix composition, nuclear YAP and patient survival, concordant with vocal fold cancer sensitivity to oncogenic YAP-TEAD Hippo pathway inhibitors both in vitro and in vivo. Overall, our findings suggest that vocal fold cancer is a mechanically sensitive malignancy, and that the restoration of tumour mechanophenotype or YAP/TAZ targeting represents a tractable anti-oncogenic therapeutic avenue for vocal fold cancer.