Abstract B109: Heterogeneity of S100A2, KRT17, and KRT5 in donor Pancreatic Intra-epithelial neoplasia and donor-derived Organoids

The overall 5-year survival rate of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC)is very low (13%), due to late diagnosis and poor treatment outcomes. For this reason, there is a strong emphasis on early detection of this disease. Pancreatic Intraepithelial Neoplasia (PanIN) is the most common precursor for pancreatic cancer. We recently showed that PanINs are common in individuals across age groups; as PanIN prevalence is much higher than previously expected, while pancreatic cancer is rare, it follows that most PanINs will not progress to malignancy. In partnership with Gift of Life Michigan, we have expanded our cohort to 115 donor pancreata (age range: 21 to 76 years); this larger number of samples allowed us to investigate whether PanIN show heterogeneity that might portend differential progression risk. For this purpose, we did single-cell RNA sequencing (scRNA-seq) and GeoMx. We also generated organoid cultures from the donor pancreata. We then stained tissue from multiple donors using immunofluorescence and imaged them by confocal microscopy. Across all donor pancreata, only two presented with histologically high-grade PanIN, while the remaining had only low-grade lesions; overall, 60% of pancreata presented with PanIN. Although histologically PanIN were largely low-grade, immunostaining revealed unexpected heterogeneity. Namely, some lesions contained cluster of cells, of variable size, expressing markers usually associated with basal, aggressive pancreatic cancer such as S100A2, KRT5, KRT17, CXCL1 and CXCL8. The GeoMx and analysis of scRNA-seq data confirmed the presence of KRT5, KRT17, and S100A2 in PanIN cells. Lastly, this specific profile was also found in a subgroup of normal pancreas, donor-derived, organoids, and was associated with differential stromal composition. Additionally, PanIN also differed in terms of proliferation status, with some lesions being largely quiescent while others having variable expression of KI67. Overall, our work reveled unexpected heterogeneity in human PanIN lesions; future studies will address whether PanIN heterogeneity reflects different genomic alterations, and whether it portends a higher risk of progression to malignancy. Citation Format: Jude O. Okoye, Alexander Bray, Rosina A. Carr, Padma Kadiyala, Ahmed M. Elhossiny, Eileen S. Carpenter, Timothy Frankel, Marina Pasca Di Magliano. Heterogeneity of S100A2, KRT17, and KRT5 in donor Pancreatic Intra-epithelial neoplasia and donor-derived Organoids [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B109.