Abstract 1623: Mechanistic insights into low-frequency ultrasound-induced cancer cell apoptosis

Abstract Cancer cells undergo rigidity independent growth due to low expression of mechanosensory cytoskeletal protein known as tropomyosin 2.1, acting as rigidity sensing module. This enables their survival on soft matrices by inciting distinct response to the mechanical cues, in contrast to non-transformed cells. We previously found that treatment of cancer cells with low-frequency ultrasound results in calcium influx through activation of piezo1 channels, microtubule depolymerization through calpain proteases, activation of RhoA-ROCK pathway and increased myosin IIA-mediated actomyosin contractility, ultimately causing cell death in calcium-induced calcium release manner. However, the underlying processes connecting the initiation of apoptosis upon mechanical stimuli remain inadequately understood. Our research focus involves ER-mitochondrial stress pathway comprising of mitochondria-associated ER membranes (MAMs), that might be involved in causing apoptosis in cancer cells exhibiting variations in their mechanoresponse via differential cell killing, while leaving the normal cells unaffected. Recently, we found lowering of mitochondrial membrane potential in cancer cells post-ultrasound treatment. Mitochondrial distribution of normal and cancer cells after ultrasound treatment varied dramatically, leading to increased punctate forms in cancer cells. Inhibition of mitochondrial fission showed significant decrease in apoptosis of cancer cells after ultrasound treatment. We conclude crucial role of mitochondrial fission, ROS and electron transport chain in low-frequency ultrasound-mediated apoptosis in cancer cells along with the cytoskeletal proteins. Tuning of desired parameters involving frequency, pressure and pulse duration could aid in the development of non-invasive cancer therapeutics. Citation Format: Aditi Singh, Felix Margadant, Michael Sheetz. Mechanistic insights into low-frequency ultrasound-induced cancer cell apoptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1623.