Abstract C141: Race-dependent epigenetic restoration of acinar identity in normal human pancreatic 3D organoids

Abstract

Pancreatic cancer is preceded by acinar-to-ductal metaplasia (ADM), an early precursor event. ADM is tightly controlled epigenetically by DNA methylation and histone acetylation; active Hippo signaling also regulates ADM. We explored the ability of three classes of compounds to promote acinar re-expression in a 3D organoid model of ADM. Following the establishment of 3D organoids from normal human acinar tissue, cultures were treated with 1 µM and 500 nM of the HDAC inhibitors romidepsin and trichostatin A (TSA) for 2 days. In parallel, acinar cultures were treated from Day 0 with a combination of the DNA methyltransferase inhibitor decitabine (10 nM, spiked in daily) and a potent, covalent inhibitor of TEAD-mediated transcription, CV-4-26 (10 µM), for 2 days. Additionally, we evaluated proteolysis-targeting chimeras (PROTACs); bifunctional molecules that recruit an E3 ubiquitin ligase to a target protein to drive its selective proteasomal degradation, using a 3-day treatment with an HDAC8-targeting PROTAC (YL352) and a dual HDAC3/8-targeting PROTAC (YX968). Viability was assessed by LIVE/DEAD staining. Acinar reexpression was assessed by increased AMY2A and reduced KRT19 mRNA expression, with decitabine/CV-4-26 producing a 25-fold increase in AMY2A and a 10-fold decrease in KRT19. Romidepsin and TSA combination caused a ∼10-fold induction of AMY2A and ∼10-fold suppression of KRT19. As our prior studies indicated that acinar re-expression following HDAC inhibition differed by donor race, we examined the ability of the PROTACs to promote acinar re-expression in organoids from Black, White, and Hispanic donors. The PROTAC to HDAC8 produced a race-dependent increase in the AMY2A/KRT19 ratio in the order of Black < White < Hispanic donors. Since maintenance of acinar identity suppresses cellular plasticity and limits ADM, restoration of acinar gene expression represents a promising differentiation-based therapeutic strategy for early pancreatic cancer. Md Abu T. Siddique, Jinmai Jiang, Anrew A. Brock, Chenglong Li, Guangrong Zheng, Thomas D Schmittgen. Race-dependent epigenetic restoration of acinar identity in normal human pancreatic 3D organoids [abstract]. In: Proceedings of the 19th AACR Conference on the Science of Cancer Health Disparities; 2026 Oct 18-21; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2026;35(10 Suppl):Abstract nr C141.