Abstract 1424: Delineating pancreatic ductal adenocarcinoma risk using stem cell derived exocrine pancreas organoids

Abstract Pancreatic ductal adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer-related deaths by the end of this decade. There is an urgent need to improve risk stratification for prevention and diagnosis and identify novel targets for therapeutic intervention. Both epidemiological factors and genetic variants influence PDAC risk. Epidemiological risk factors include obesity, type 2 diabetes, smoking, and pancreatitis, all of which are associated with inflammation. Genome-wide association studies (GWAS) for PDAC have identified common risk variants with small effect sizes at over 20 loci. Most variants lie in non-coding regions of the genome and thus, the mechanism underlying risk is not obvious. Often enriched in gene regulatory elements, it is thought that the variants influence risk through allele-specific effects on gene regulatory mechanisms, which require extensive follow-up studies. Gene regulatory elements mediate cell-type and stimulus-specific transcriptional programs. Thus, it is crucial to study germline risk variants in models that accurately represent the environment where they exhibit their effects. In an effort to improve our model system for post-GWAS functional studies beyond PDAC-derived cell lines, we have implemented an inducible pluripotent stem cell (iPSC) differentiation protocol to develop exocrine pancreas organoids comprised of acinar and duct-like cells. Preliminary studies demonstrate an enrichment of acinar (CPA1, CTRC, AMY2b) and duct (SOX9, KRT19, CA2) cell markers relative to iPSCs in both the pancreatic progenitor and exocrine organoid cell populations using quantitative PCR. This was further confirmed using immunofluorescence staining of the organoids for CPA1 (acinar), KRT19 (duct) and ongoing flow cytometry analysis. Using Paired-Seq, we are characterizing the chromatin accessibility and transcriptome of the organoids at single-cell resolution to map their gene regulatory elements and compare them to those of PDAC-derived cell lines and FACS-sorted primary exocrine cells. Additionally, we are optimizing different conditions using exogenous cytokine treatment of the organoids to create an in vitro system that better resembles an environment conducive to PDAC tumorigenesis. Implementing an iPSC-derived exocrine pancreas model for post-GWAS functional studies opens the door for improved, more in depth functional characterization of risk variants, including how they interact with the cellular environment. This work will help identify risk mechanisms and new therapeutic targets and assist in improving risk stratification of patients. Citation Format: Katelyn Elizabeth Connelly, Minal Patel, Gauri Prasad, Thuc Nhi Truong Vo, H. Efsun Arda, Laufey Amundadottir. Delineating pancreatic ductal adenocarcinoma risk using stem cell derived exocrine pancreas organoids [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 1424.