Ultrasound‐mediated mechanical forces activate selective tumor cell apoptosis

Recent studies show that tumor cells undergo apoptosis after mechanical stretching, which promotes normal cell growth. Since ultrasound can produce similar sub‐cellular mechanical stresses on the nanoscale, here we test the effect of ultrasound‐mediated mechanical forces on tumors and normal cell survival. Surprisingly, tumor cells undergo apoptosis through a calpain‐dependent mitochondrial pathway that relies upon calcium entry through the mechanosensitive Piezo1 channels. This is a general property of all tumor cell lines tested irrespective of tissue origin, but normal cells are unaffected. In vivo, ultrasound treatment promotes tumor cell killing in a mouse model with invasive CT26 cancer cell subcutaneous tumors and in the chick chorioallantoic membrane (CAM) model with relatively minor damage to chick embryos. Further, patient‐derived pancreatic tumor organoids are killed by ultrasound treatment. Because ultrasound‐mediated mechanical forces cause apoptosis of tumor cells from many different tissues in different microenvironments, it may offer a safe, non‐invasive approach to augment tumor treatments.