Selective killing of cancer-associated fibroblasts by ultrasound-mediated mechanical forces

Recent studies show that stretch/ultrasound (US)-generated mechanical forces cause selective apoptosis in several cancer cells, tumor organoids and animal models without damaging normal cells. Cancer-associated fibroblasts (CAFs) are an integral tumor microenvironment (TME) constituent. They display altered biomechanical properties similar to cancer cells, such as matrix secretion and its remodelling, chemokine secretion, and high contractile force generation. We thus test the effect of US-mediated mechanical forces on patient-derived CAF survival. Surprisingly, US treatment causes CAF apoptosis (mechanoptosis) through a calcium-activated apoptotic pathway but not in normal fibroblasts. MicroRNA-21 (miR-21) secreted by primary cancer cells suppresses the mechanosensory cytoskeletal protein tropomyosin 2.1 (Tpm2.1) in CAFs. This Tpm2.1 depletion in CAFs is responsible for mechanoptosis. Interestingly, normal fibroblasts behave similarly when Tpm2.1 was depleted. Further, 3D gel contractility and migration assay confirm that a prolonged US treatment disrupts myosin IIA-mediated contractility, which CAFs primarily use to support cancer invasion. Since US treatment causes mechanoptosis and reduces contractility, this approach could be used to develop ultrasound-based CAF-targeting therapy to augment cancer treatment.