Cytosolic Phospholipase A2 Determines Intercellular Heterogeneity of Stress Granules and Chemotherapy Response Available to Purchase

Cancer cell heterogeneity is a major therapeutic challenge. In this study, we identify that individual cells within cancer cell populations show significant heterogeneity in the levels of the stress-adaptive organelles, stress granules (SG), and demonstrate that SG heterogeneity is dictated by the cell cycle state. Specifically, SG formation is distinctively heightened in cells in the G₂ phase because of the interplay between a nonapoptotic function of CASPASE-3 and calcium-dependent phospholipase A2 (cPLA2)–mediated production of the SG-promoting molecule, 15-deoxy-delta-prostaglandin-J2. We demonstrate that in the G₁–S phase, CASPASE-3 cleaves and inactivates cPLA2, whereas in the G₂ phase, CASPASE-3 activity is suppressed, resulting in enhanced cPLA2 activity and 15-deoxy-delta-prostaglandin-J2 upregulation. We show that cell cycle–dependent SG heterogeneity is a property of pancreatic ductal adenocarcinoma and targeting G₂-SGs by inhibiting cPLA2 sensitizes pancreatic ductal adenocarcinoma 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.

Because of their defective G₁ checkpoint mechanisms, cancer cells often activate a G₂ checkpoint, which leads to resistance to DNA-damaging chemotherapeutics. We identify an intercellular heterogeneity of SGs that is driven by the cell cycle, with SG formation being highest in the G₂ phase. Targeting G₂-specific SG formation sensitizes pancreatic tumors to G₂ arrest–inducing chemotherapeutics.