The Role of Protein Phosphatase 2A in Nutrient Scavenging and Plasticity of Pancreatic Ductal Adenocarcinoma

<p dir="ltr">Nutrients in the pancreatic ductal adenocarcinoma (PDAC) microenvironment are commonly depleted, with the vital amino acid glutamine among the most deficient metabolites. To circumvent this deprivation, PDAC cells initiate KRAS dependent macropinocytosis, an actin-driven nutrient scavenging pathway. As glutamine is essential for PDAC cell survival, therapeutic inhibition of macropinocytosis represents a novel strategy to suppress nutrient acquisition and drive cell death.</p><p dir="ltr">Protein phosphatase 2A (PP2A) is a heterotrimeric Serine/Threonine phosphatase known to inhibit downstream targets of the KRAS signaling cascade and is implicated in macropinocytosis regulation. Using high molecular weight Dextran, we demonstrate pharmacological activation of PP2A promotes macropinosome accumulation in cells. This accumulation was caused by the inability of macropinosomes to fuse with lysosomes, leading to cell death. The fusion of macropinosomes with lysosomes is a dynamic process that can be mediated by the lipid kinase, PIKfyve. Using co-immunoprecipitation, we established that PP2A interacts with PIKfyve and that the activation of PP2A was associated with differential phosphorylation of PIKfyve on three key serine residues, S299, S1167 and S1754. Finally, we determine that PP2A activating compounds can function synergistically with metabolic inhibitors and significantly suppress tumor growth <i>in vivo</i>. Together, these findings indicate that activation of PP2A in PDAC promotes aberrant macropinocytosis by preventing lysosomal fusion potentially through PIKfyve regulation. This regulation highlights the use of PP2A activating compounds as potential therapeutics to prevent nutrient scavenging in PDAC.</p>