Abstract A003: APOBEC3A drives chromosomal instability and tumor evolution in pancreatic cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy marked by extensive genomic complexity, early dissemination, and resistance to therapy. APOBEC3A (A3A), a cytidine deaminase, has emerged as a candidate driver of chromosomal instability (CIN) and intertumoral heterogeneity (ITH), yet its role in PDAC evolution remains incompletely defined. To address this gap, we have assembled a comprehensive dataset that integrates genetically engineered mouse models, human PDAC tissues, and established cancer cell lines. The engineered mouse models were specifically designed to represent distinct biological scenarios of A3A activity, providing a systematic framework to dissect its impact on tumor evolution. Complementary data from human tissues and cell lines will validate these findings in clinically relevant contexts, ensuring direct translational significance. In addition, we have optimized and tested a laser-capture microdissection (LCM) approach that enables spatially resolved sampling of multiple regions within human tumors, thereby facilitating high-resolution analyses of clonal dynamics and their relationship to A3A activity. With these resources in place, we will apply bulk whole-genome sequencing (WGS) and advanced computational pipelines to identify A3A-associated copy number signatures. By integrating cross-species models with high-resolution human sampling, we aim to reveal how A3A mediates the transition from pre-neoplastic lesions to advanced PDAC and to uncover potential vulnerabilities that could be therapeutically targeted. This work will establish a systematic and clinically validated framework for evaluating A3A as a driver of genomic instability in PDAC, ultimately guiding strategies to mitigate heterogeneity and improve patient outcomes. Citation Format: Zhihui Zhang, Chunxu Gao, Ashwath Seetharaman, Norbert Kreisz, Abhijnan Chakraborty, Vince Bernard. Pagan, Alexander Semaan, Anirban Maitra, Fredrik Thege, Mia Petljak, Sonja M. Wörmann, Peter Van Loo. APOBEC3A drives chromosomal instability and tumor evolution in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr A003.