Activation of PP2A-B56a leads to aberrant EGFR signaling and proliferative phenotypes in PDAC.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) stands to become the second most deadly cancer by 2030. Mutations in the small GTPase, KRAS, occur in over 90% of PDAC patients and drive signaling plasticity through phosphorylation cascades. Protein phosphatases are master regulators of signal transduction, yet the contribution of phosphatase dysregulation to mutant KRAS phenotypes is poorly understood. Protein phosphatase 2A (PP2A) inhibits KRAS effectors, placing this family of enzymes as key regulators of PDAC signaling. However, we previously demonstrated that pharmacological activation of PP2A elicits heterogeneous responses in PDAC cells, with some cell lines displaying augmented oncogenic signaling despite increased phosphatase activity. Here, we determined the impact of the specific PP2A subunit, B56a, on PDAC phenotypes using both genetic and pharmacological activation strategies in human PDAC cell lines and genetic mouse models. We demonstrate that B56a knockout reduces PDAC proliferation while exogenous expression exacerbates proliferative phenotypes. This increase in proliferation predominately occurs through epidermal growth factor receptor (EGFR), a critical signaling node associated with poor patient outcome. The activation of EGFR by PP2A-B56a is mediated through increased expression and processing of EGFR ligands, such as amphiregulin. In vivo, the genetic loss of Cip2a, an endogenous PP2A inhibitor, significantly increases EGFR activation and decreases overall survival. Finally, pharmacological activation of PP2A leads to increased EGFR signaling in tumors; however, EGFR inhibition mitigates this signaling and significantly decreases tumor growth compared to single-agent treatment alone. Together, these studies implicate a previously undescribed non-canonical role for PP2A-B56a in EGFR signaling that contributes to PDAC progression.