Abstract PR-008: The role of PP2A-B56α in acinar-to-ductal metaplasia and initiation of pancreatic ductal adenocarcinoma

Abstract

Abstract Protein phosphatase 2A (PP2A) is a major serine-threonine phosphatase that regulates many cellular pathways including KRAS, whose oncogenic mutation is prevalent in 95% of patients with Pancreatic Ductal Adenocarcinoma (PDAC). Previous research has identified a decrease in global PP2A activity and an increase in the expression PP2A inhibitors in PDAC cell lines, suggesting that suppression of PP2A activity may be pertinent in PDAC maintenance. Importantly, PP2A has low mutation rates in PDAC, making it a viable target for therapeutic reactivation. While PP2A has been shown to have global tumor suppressive capabilities, the regulation of specific pathways by PP2A can be altered based on PP2A holoenzyme composition. Therefore, there is a critical need to understand the mechanisms by which oncogenic KRAS can affect PP2A function and differential substrate targeting in PDAC. The PP2A holoenzyme consists of 3 subunits: the scaffolding subunit (A), the catalytic subunit (C), and the regulatory subunit (B). There are 16 different B subunits that can be incorporated into the PP2A holoenzyme that are responsible for substrate specificity. The B56α subunit of PP2A has been shown to negatively regulate cellular transformation and has decreased expression in aggressive subtypes of PDAC, indicating that suppression of this subunit may aid in PDAC tumorgenicity. Our research aims to investigate the mechanisms by which PP2A-B56α is regulated downstream of oncogenic KRAS and how suppression of B56α impacts the initiation and progression of PDAC. In order to determine how oncogenic KRAS alters the dynamics of PP2A-B56α and overall PP2A activity we utilized tet-inducible KRASG12D cell lines to allow direct manipulation of KRAS mutational activation. Using this system, we have identified time dependent alterations in cancerous inhibitor of PP2A (CIP2A) following induction of KRASG12D expression, indicating that PP2A suppression may be an early event in PDAC initiation. Consistent with this hypothesis, we characterized changes in the acceleration of PDAC formation in vivo using the Ptf1a-Cre; LSL-KRASG12D (KC) genetic mouse model combined with a B56α hypomorph model (KCBhm/hm). Our data show that the loss of B56α accelerates PDAC initiation, with an increase in pancreatic precursor lesion (PanIN) number and a decrease in healthy acinar area. Similar results were seen in an ex vivo acinar-to-ductal metaplasia assay, suggesting that B56α alters pancreatic cellular plasticity in a cell-autonomous manner. Future studies will investigate how mutant KRAS expression effects overall PP2A phosphatase activity, holoenzyme formation, and sequestration of B56α by endogenous inhibitors to further understand how suppression of PP2A-B56α contributes to development of PDAC. Together, these studies identify PP2A as a critical regulator of KRAS-induced cellular plasticity and support therapeutic reactivation of PP2A as a novel therapeutic strategy in PDAC patients. Citation Format: Samantha L. Tinsley, Rebecca A. Shelley, Mary C. Thoma, Goutham Narla, Rosalie C. Sears, Brittany A. Allen-Petersen. The role of PP2A-B56α in acinar-to-ductal metaplasia and initiation of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr PR-008.