Pharmacological Activation of Myosin II to Correct Pancreatic Cancer Cell Mechanics

Abstract

Pancreatic ductal adenocarcinoma (PDAC) annually affects 44,000 people in the U.S. and has an abysmal five-year survival rate of around 6%, which is nearly unchanged over the past 40 years. Pharmacological strategies for treating cancer have primarily focused on inhibiting cell growth through specific genetic pathways, which typically either fail to abolish the disease or lead to compensatory regulatory changes and subsequently, to drug resistance. Importantly, alterations in mechanical properties are a common feature of cancer cells, yet targeting cell mechanics remains an under-utilized approach for drug development.Here we develop a system for targeting cell mechanics for the discovery of novel therapeutics. We designed a live-cell, high-throughput chemical screen to identify mechanical modulators in Dictyostelium discoideum. We characterized 4-hydroxyacetophenone (4-HAP), which increases the cellular cortical tension by enhancing the cortical localization of the mechanoenzyme myosin II, independent of myosin heavy-chain phosphorylation regulation. To shift cell mechanics, 4-HAP requires myosin II, including its full power stroke. We further establish that changes in key cytoskeletal protein distributions correlate with the changes in the biomechanical profile of PDAC progression. In addition to actin-crosslinkers, we detect that non-muscle myosin II distributions vary across PDAC states: specifically myosin IIA increases, myosin IIB decreases, and myosin IIC increases in metastatic cells. We further demonstrate that invasive pancreatic cancer cells are more deformable than normal pancreatic ductal epithelial cells, a mechanical profile that was partially corrected with 4-HAP. Tests of 4-HAP in mouse models of metastatic pancreatic disease are underway. Overall, 4-HAP modifies nonmuscle myosin II-based cell mechanics across phyla and disease states and provides proof-of-concept that cell mechanics offer a rich drug target space, allowing for possible corrective modulation of tumor cell behavior.