Abstract 3446: Acinar to ductal metaplasia is an evolutionary dead end and does not actively contribute to pancreas regeneration after damage

Abstract One of the major risk factors strongly associated with PDAC is pancreatitis and meta-analysis studies have revealed that inflammation of the pancreas increases the relative risk of developing pancreatic cancer by up to 13-fold. During pancreatitis, acinar cells transiently undergo metaplasia known as acinar to ductal metaplasia (ADM). It is well known that in the presence of activated oncogenes, for example mutated Kras, this metaplastic state can progress into PDAC with ADM being the first step towards tumorigenesis. To understand the pathophysiological role of ADM during pancreatitis and tumorigenesis, we utilized different mouse models to study the function and fate of ADM cells. We found that although ADM can effectively mitigate pancreatitis-induced tissue damage, it is not a regenerative process. Instead, cells that underwent ADM were eventually exhausted. We confirmed these findings by performing lineage tracing experiments to understand the fate of the cells and found that they were indeed not responsible for regenerating the pancreas. To better capture the dynamic process distinct sub-populations of epithelial cells undergo, during ADM induction and resolution, we are leveraging spatial transcriptomics of the entire pancreatic tissue at different timepoints after damage induction. We are also actively studying how oncogenic Kras activation reverts this process and contributes to tumorigenesis. This study will shed light on initiation of pancreatic cancer and how it can be prevented in the context of evolution from pancreatitis. Citation Format: Rutvi Shah, I-Lin Ho, Er-Yen Yen, Charles Dyke, Hyuk Jean Kwon, Matthew Wong, Francesca Citron, Zhaoliang Liu, Sergio Attanasio, Ruparoshni Jayabalan, Ricardo Gonzalez Delgado, Luca Cecchetto, Elisabetta Granato, Ashish Damania, Shan Jiang, Haoqiang Ying, Giulio Draetta, Mauro Di Pilato, Nadim Ajami, Andrea Viale. Acinar to ductal metaplasia is an evolutionary dead end and does not actively contribute to pancreas regeneration after damage [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 3446.