Abstract 7083: Classical and basal like cells in donor tissues reveal phenotypic heterogeneity of pancreatic intraepithelial neoplasia

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease that affects individuals of all ages, with marginal improvements in patient survival rates over the years despite available treatments. Although Pancreatic Intraepithelial Neoplasia (PanIN), an early lesion, is known to precede PDAC, identifying individuals at risk of developing PDAC remains a challenge for clinicians. Recent studies have demonstrated both inter- and intra-heterogeneity of PDAC, as well as the aggressive nature of its phenotypes, but little is known about the heterogeneity of PanIN and its risk of progression in humans. To address this gap, we investigated transplant-incompetent samples from 89 male and female White and African-American patients, ages 21 to 76 years, collected through the Gift of Life program. Pathologic analyses using basic histological techniques revealed an average burden of three PanINs per 2 cm x 2 cm of donor tissue. Single-cell RNA sequencing and protein validation identified distinct classical and basal-like cells, along with expression of cytokines that correlate to the phenotypes previously reported in PDAC. In some patients, subpopulations within the already-established aggressive basal cells were identified. Regardless of cell phenotype, the senescence state of most of the identified PanINs may explain why these patients were not diagnosed with PDAC during their lifetimes. Given that most PDAC develop from PanIN and PanINs are often found adjacent to tumors, we are currently probing upregulated and downregulated pathways in tumor-associated PanINs and donor PanINs with tumor-like features, as well as crosstalk between classical and basal PanINs and their microenvironments. We are also developing a model to provide further insight into the risk of disease progression using spatial transcriptomic analysis. This knowledge could lead to more effective methods for early detection and treatment of the lethal disease. Citation Format: Jude O. Okoye, Rosina Carr, Ahmed M. Elhossiny, Alberto C. Olivei, Imade Williams, Lei Sun, Yaqing Zhang, Eileen S. Carpenter, Timothy L. Frankel, Marina Pasca Di Magliano. Classical and basal like cells in donor tissues reveal phenotypic heterogeneity of pancreatic intraepithelial neoplasia [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 7083.