Cytosolic Phospholipase A2 determines Intercellular Heterogeneity of Stress Granules and Chemotherapy Response

Abstract Cancer cell heterogeneity is a major therapeutic challenge. Here, we identify that individual cells within cancer cell populations show significant heterogeneity in the levels of the stress-adaptive organelles, stress granules (SGs), and demonstrate that SG heterogeneity is dictated by cell-cycle state. Specifically, SG-formation is distinctively heightened in cells in G2-phase due to the interplay between a non-apoptotic function of Caspase 3 and calcium-dependent phospholipase A2 (cPLA2)-mediated production of the SG-promoting molecule, 15-deoxy-delta-prostaglandin-J2 (15d-PGJ2). We demonstrate that in G1/S phase, Caspase 3 cleaves and inactivates cPLA2, whereas in G2-phase, Caspase 3 activity is suppressed, resulting in enhanced cPLA2 activity and 15d-PGJ2 upregulation. We show that cell-cycle-dependent SG heterogeneity is a property of pancreatic ductal adenocarcinoma (PDAC) and targeting G2-SGs by inhibiting cPLA2 sensitizes PDAC to G2-arrest-inducing chemotherapeutics. Our findings highlight cell-cycle-dependent SG formation as a fundamental property of SGs, a key aspect of cancer heterogeneity, and a target for cancer treatment.