Abstract 7501: APOBEC3A drives chromosomal instabilityand tumor evolution in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer characterized by extensive genomic complexity, rapid metastasis, and resistance to therapy. Our research focuses on the role of APOBEC3A (A3A), a cytidine deaminase enzyme, in promoting chromosomal instability (CIN) and intratumoral heterogeneity (ITH) as mechanisms driving PDAC progression and metastasis. Preliminary findings reveal that A3A drives CIN in a deaminase-independent manner, as demonstrated by dose-dependent increases in structural variants, micronuclei formation, and chromosomal aberrations. Furthermore, A3A expression significantly correlates with early tumor dissemination, enhanced metastatic colonization, and reduced survival, as shown in both human and murine models. While previous studies have highlighted A3A's molecular effects, they lack copy number signature analysis to systematically characterize CIN. Addressing this gap, our study aims to define A3A-driven copy number signatures in PDAC, providing critical insights into its role in tumor evolution and vulnerability to therapeutic interventions. Using a multi-modal approach, we integrate data from genetically engineered mouse models, human PDAC tissues, and cancer cell lines, employing bulk whole-genome sequencing (WGS) and advanced bioinformatics pipelines to uncover the full scope of A3A’s contributions to tumor evolution. We aim to demonstrate how A3A-mediated genomic instability accelerates the transition from pre-neoplastic lesions to advanced PDAC. Our findings will elucidate how A3A-mediated genomic instability accelerates the progression from pre-neoplastic lesions to advanced PDAC. By addressing critical gaps in the understanding of CIN and ITH, this study positions A3A as a compelling therapeutic target to mitigate genomic instability, reduce tumor heterogeneity, and ultimately improve clinical outcomes for patients with pancreatic cancer. Citation Format: Zhihui Zhang, Chunxu Gao, Sonja Wörmann, Peter Van Loo. APOBEC3A drives chromosomal instabilityand tumor evolution in pancreatic cancer [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 7501.