Abstract C062: Investigating the role of pancreatic intraepithelial neoplasia in development of pancreatic ductal adenocarcinoma

Abstract

Abstract Pancreatic ductal adenocarcinoma (PDA) is a dismal disease with a 5-year survival rate of 11%. This poor prognosis is due in part to a lack of early disease detection and resistance to current therapies. The most common PDA precursor is pancreatic intraepithelial neoplasia (PanINs); a microscopic lesion that cannot be detected by imaging. Accumulation of a series of genomic mutations in pancreatic exocrine cells leads to formation of PanINs through mechanisms that remain unknown. While PanIN development has been well-studied in genetically engineered mouse models, its onset and pathogenesis in humans has remained elusive due to the inability to study tissue from pathologically normal pancreases. Due to its abundance in digestive enzymes, the pancreas degrades shortly after death and autopsy samples are not suitable for several research applications that require fresh tissue. Through collaboration with the Gift of Life Organ and Tissue donation program, we performed histological and transcriptomic analysis on ten normal pancreata that were refused for transplant. Histological analysis revealed the presence of PanIN lesions in 6 of the 10 donors as early as 25 years of age. To delineate the molecular, cellular, and spatial composition of PanIN lesions to those from acinar and ductal cells we combined single cell RNA sequencing analysis with spatial transcriptomics for the same sample. Annotation of cellular composition of distinct tissue regions demonstrated that PanIN transcriptome closely resembled that of invasive PDA. Using differential expression analysis, we identified factors that were highly expressed in PanINs, but not expressed in normal acini or ducts. We validated the transcript-based findings with immunostaining and RNA in-situ hybridization. We then sought to characterize the microenvironment of the normal pancreas and of PanIN lesions using multiplex immunohistochemical analysis. We observed abundant fibroblasts and macrophages in normal areas of the pancreas as well as surrounding PanIN lesions, while T cells were limited to the latter. Currently, we are characterizing the transcriptome profile of macrophages and fibroblasts. Uncovering the factors that promote the development of sporadic PanINs and their progression to malignancy could aid in designing preventative strategies for high-risk individuals. Citation Format: Padma Kadiyala, Eileen Carpenter, Ahmed Elhossiny, Yaqing Zhang, Sarah Nelson, Fatima Lima, Katelyn Donahue, Wenting Du, Jake McGue, Hannah Watkoske, Holly Attebury, Donnele Daley, Filip Bednar, Arvind Rao, Timothy Frankel, Marina Pasca Di Magliano. Investigating the role of pancreatic intraepithelial neoplasia in development of pancreatic ductal adenocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C062.