Abstract B106: Elucidating the clonal dynamics and epigenetic regulators of PDAC initiation in inducible neoplastic organoid models

Abstract Pancreatic intraepithelial neoplasms (PanINs), precursor lesions of pancreatic ductal adenocarcinoma (PDAC) that are abundant healthy individuals, rarely progress to cancer despite universally possessing many of the driver alterations associated with malignancy. Recent single cell profiling efforts of PanIN progression in vivo have described marked heterogeneity in chromatin accessibility and transcriptional identity within these neoplasias, but it remains unclear how discrete epigenetic factors play a role in shaping tumorigenesis, or what distinguishes rare neoplastic cells capable of seeding invasive carcinomas from their benign neighbors. Given that more than 80% of patients with PDAC present with unresectable or metastatic disease, further studies on the molecular features of PanIN progression are needed to enable methods of early detection and intervention. Unfortunately, owing to their microscopic size and challenges associated with the isolation of PanINs from surrounding normal epithelium and stroma, it is particularly difficult to address these knowledge gaps in vivo. By generating complex murine derived organoid models, we have built a system that allows us to faithfully reconstitute the evolution from benign PanIN to PDAC in vitro, as well as in vivo through orthotopic implantation into syngeneic mice. As they are easily perturbable, readily generate large amounts of biomass, and closely resemble the stages of PDAC initiation in vivo, these models can be leveraged to directly assay how chromatin remodelers influence malignant transformation. Further, pairing these organoids with our highly multiplexed, transcribable DNA barcoding system and single cell epi multiomics will enable us to study the evolutionary dynamics, chromatin landscapes, and transcriptional identities of clonal populations of PanIN organoids as they progress to cancer. Through these studies, we will gain unprecedented insights into the underpinnings of PDAC initiation, and thus may open up new avenues for the early detection of tumorigenesis. Citation Format: Connor J. Hennessey, Minh T. Than, Ben Z. Stanger, Sydney M. Shaffer. Elucidating the clonal dynamics and epigenetic regulators of PDAC initiation in inducible neoplastic organoid models 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 (18Suppl₃): Abstract nr B106.