Abstract 5139: PP2A-B56a as a critical regulator of cellular plasticity and epithelial-to-mesenchymal transition

Abstract Metastasis is the major cause of death in cancer patients including lung cancer, the leading cause of cancer-related deaths in the United States. Fifty percent of patients have metastatic disease at the time of diagnosis, plummeting the 5-year survival rate from 26% to just 9%, demonstrating a critical gap in our understanding of the contributing cell signaling pathways. Epithelial-to-Mesenchymal Transition (EMT) is an important initiating step in metastasis, allowing cells to become more migratory and invasive to establish secondary tumors in distant locations. Previous studies have identified transcriptional reprogramming as the main driver of EMT. While transcription factors are important in this cell state switch, there are many factors that contribute to EMT outside of transcriptional regulation, such as post-translational modifications (PTMs). PTMs, such as phosphorylation, play a large role in cell signaling that can impact cellular identity and plasticity, yet these modifications are largely understudied, particularly in the context of EMT. The serine/threonine phosphatase, Protein Phosphatase 2A (PP2A), is a vital phosphatase, accounting for 50% of serine/threonine phosphatase activity in the cell. PP2A is a heterotrimeric complex consisting of a scaffolding subunit (A), a catalytic subunit (C), and regulatory subunit (B) which determines substrate specificity. Though PP2A has previously been shown to play a role in cell state regulation and EMT, the contribution of the individual B subunits is unknown. PP2A-B56α has previously been implicated in tumor suppression and the regulation of cellular plasticity. Through the use of 2D immunofluorescence, western blot analysis, and 3D invasion assays, our in vitro studies show that loss of PP2A-B56α leads to a significant alteration in cell identity, demonstrated by a reduction in epithelial markers (E-cadherin) and an increase in mesenchymal markers (Vimentin). These shifts in cell markers also correlate with enhanced migratory and invasive capabilities in vitro and are recapitulated in vivo via tail vein invasion assay. Collectively, these findings highlight PP2A-B56α as a key regulator of cellular plasticity and EMT in lung cancer. Citation Format: Brittany N. Heil, Claire M. Pfeffer, Garima Baral, Mei B. Bahler, Anna K. Darling, Sydney J. Clifford, Brittany L. Allen-Petersen. PP2A-B56a as a critical regulator of cellular plasticity and epithelial-to-mesenchymal transition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5139.