Abstract C079: Exploring acinar to ductal metaplasia in pancreatitis and precancerous contexts using FixNCut

Abstract Acinar to ductal metaplasia (ADM) is the process by which acinar cells transition to a duct-like state acquiring ductal markers and morphology. This process can be driven by pancreas inflammation or injury, such as pancreatitis, where it is thought to be an adaptive response to help mitigate damage and facilitate repair. ADM is also observed following acinar-specific oncogenic KRAS mutations and known to precede PDAC precancerous lesions termed pancreatic intraepithelial neoplasias (PanINs). While ADM is well characterized histologically, cellular and molecular details of ADM and PanIN formation remain less well understood, in part due to high levels of digestive enzyme production in acinar cells that hamper characterization. Leveraging our recently described DSP-fixation method, FixNCut, to improve capture and transcriptome quality of acinar and ADM populations in the pancreas, we characterize ADM arising in three contexts: acute pancreatitis, recurrent acute pancreatitis, and acute pancreatitis with an oncogenic KRAS mutation known to drive the formation of PanINs. FixNCut and single-cell RNA-sequencing enabled us to elucidate the transcriptomic landscape of ADM and define changes to the microenvironment in unprecedented detail. Our findings indicate that the cellular and transcriptional landscape of recurrent acute pancreatitis closely mirrors that of acute pancreatitis for up to 6 weeks (or 6 bouts of 2-day acute pancreatitis), which was the longest timepoint tested. In contrast, acute pancreatitis in the presence of an acinar-specific oncogenic KRAS mutation results in a distinct transcriptional profile for both ADM and the surrounding microenvironment compared to pancreatitis alone. Additionally, we use FixNCut to preserve the epigenomes of acinar cells, enabling us to sort acinar cells and profile their histone modifications in various contexts of ADM. We benchmark and validate our results against existing mouse and human datasets of precancer and cancer. Through this work, we aim to enhance our understanding of ADM in various contexts, providing insights into acinar cell plasticity and early PDAC precursor formation that may inform strategies for early detection and interception. Citation Format: Katherine Aney, Woo-Jeong Jeong, Pal Koak, Isabel Kim, Sahar Nissim. Exploring acinar to ductal metaplasia in pancreatitis and precancerous contexts using FixNCut [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr C079.