Compressive Stress Enhances Invasive Phenotype of Breast Cancer Cells via Piezo1 Activation

Abstract Uncontrolled growth in solid tumor generates compressive stress that drives cancer cells into invasive phenotypes, but little is known about how such stress affects the invasion and matrix degradation of cancer cells and the underlying mechanisms. Here we show that compressive stress enhanced invasion and matrix degradation of breast cancer cells. We further identified Piezo1 as the putative mechanosensitive cellular component that transmits compressive stress to induce calcium influx, which in turn activate Src/ERK signaling. Interestingly, we observed actin protrusions with matrix degradation ability on the apical side of the cells. Furthermore, we demonstrate that Piezo1 channels were partially localized in caveolae, and reduction of caveolin-1 expression or disruption of caveolae with methyl-β-cyclodextrin led to not only reduced Piezo1 expression but also attenuation of the invasive phenotypes promoted by compressive stress. Taken together, our data indicate that mechanical compressive stress activates Piezo1 channels to mediate enhanced cancer cell invasion and matrix degradation that may be a critical mechanotransduction pathway during, and potentially a novel therapeutic target for, breast cancer metastasis.