Abstract 1438: HMGA2 and protein leucine methylation drive pancreatic cancer lineage plasticity

Abstract Pancreatic ductal adenocarcinoma (PDAC) is classified into two distinct subtypes, classical and basal. Basal PDACs (∼25% of PDACs) have the worst overall survival and are the only class to act as an independent poor prognostic factor. Therefore, there is an urgent need to understand basal PDAC development, identify biomarkers and find its unique vulnerabilities. We found high expression of the chromatin architectural protein, HMGA2 in the basal subtype of pancreatic cancer. This was across patient-derived cell lines, organoids and in RNA-seq and scRNA-seq patient datasets representing hundreds of patients. We also validated by multiplex immunohistochemistry (mIHC) in >500 diverse patient tissue microarray. We introduce a novel genetically engineered mouse model (GEMM) of basal pancreatic cancer. We find that in this model and in human orthotopic xenografts, HMGA2 is required for cancer growth and sufficient to drive a basal subtype. While HMGA2 is a chromatin factor, we have unexpectedly discovered that it plays an essential role in mRNA translation. Our data demonstrate that HMGA2 controls protein synthesis dynamics through reduced methylation of the protein phosphatase PP2A and subsequent activation of S6 Kinase, a key node of translation regulation. HMGA2 accomplishes this through inhibiting the expression of leucine carboxyl methyltransferase 1 (LCMT1). Importantly, loss of LCMT1 in the classical subtype is sufficient to increase mRNA translation and cause the acquisition of basal features. Thus, we describe a new mechanism by which lineage plasticity is regulated in pancreatic cancer. Most importantly, we demonstrate that high levels of HMGA2 in the basal subtype, and high levels of mRNA translation, render basal pancreatic cancer uniquely susceptible to inhibitors of protein synthesis. As such, we describe a new biomarker and subtype-specific treatment for basal pancreatic cancer. Citation Format: Sita Kugel, Stephanie Dobersch, Naomi Yamamoto, Aidan Schutter, Sarah M. Cavender, Tess M. Robertson, Gun Ho Jang, Annie N. Samraj, Ben Doron, Lisa A. Poole, Martine Roudier, Cindy L. Wladyka, Isabel English, Guillermo Barreto, Rosalie Sears, Srivatsan Raghavan, Faiyaz Notta, Robert N. Eisenman, Andrew C. Hsieh. HMGA2 and protein leucine methylation drive pancreatic cancer lineage plasticity [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 1438.