Abstract B022: Acinar-to-ductal metaplasia index (ADMI): A quantifiable measure of ADM

Abstract Acinar to ductal metaplasia (ADM) is thought to be a natural adaptive response to injury by which downregulation of digestive enzymes mitigates tissue damage and facilitates repair. However, this latent plasticity is also a critical gateway to cancer. In the context of a KRAS mutation – the driver mutation in pancreatic cancer – ADM is co-opted, causing acinar cells to progress into precancerous lesions instead of returning to a normal acinar state. ADM has various stages of severity marked by severe histologic changes replacing acinar morphology and markers with those of ductal epithelium. While this descriptive state of ADM is well established in pancreas biology, the field has lacked an objective measure to quantify various stages of deviation from the homeostatic acinar cell state. Here, we leverage FixNCut, a novel method for single-cell transcriptomic analysis of the pancreas, to develop an index tool that allows researchers to objectively measure the deviation of metaplastic acinar cells from normal acinar cell identity. The ADM Index, or ADMI, is based on 16 signature genes upregulated only in acinar cells in ADM, and is corroborated with GeoMx WTA data. We observe an increased ADMI score in acinar cells following pancreatitis, with perduring detectable elevation of ADM specific genes 14 days post-inflammation. ADMI was also validated in independent single-cell and bulk RNA-seq data, demonstrating the utility of scoring ADMI across studies and in diverse perturbations. We further apply ADMI to the context of recurrent weekly acute pancreatitis in mice and observe progressively increasing ADMI score sequentially at 2 week, 4 week, and 6 week timepoints. Our findings validate ADMI as a robust, objective standard that researchers can use in their own datasets to quantify deviation of individual acinar cells from normal identity, to investigate single-cell heterogeneity of these deviations, and to observe how these deviations change over time or following diverse stressors. Citation Format: Katherine J Aney, Woo-Jeong Jeong, Pal Koak, Sahar Nissim. Acinar-to-ductal metaplasia index (ADMI): A quantifiable measure of ADM [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 B022.