Abstract A029: Chromatin accessibility profiling of human pancreatic tumors reveals epigenetic features of malignant and stromal cell subtypes
Abstract
Pancreatic ductal adenocarcinoma (PDAC) disease progression involves complex cell state transitions in both malignant and non-malignant populations within the tumor microenvironment. To uncover PDAC cell states and epigenetic features associated with clinical outcome, we profiled 40 tumor samples (33 primary tumors and 7 metastases) from 39 patients with single cell ATAC-seq, along with 10 sample-matched single cell RNA-seq profiles. Through topic modeling of high dimensional chromatin data, we uncovered distinct cis-regulatory networks underlying PDAC classical, basal-like, and subtype-intermediate states. Furthermore, we delineated a core set of chromatin regions opened in all PDAC subtypes relative to ductal and acinar cells. These universally open regions showed striking overlap with gastrointestinal enhancers, highlighting a common endoderm lineage infidelity process across pancreatic tumors. Within the stromal compartment, we identified novel regulators of myofibroblastic cancer-associated fibroblasts (myCAFs) and inflammatory CAFs (iCAFs) from enhancer networks active in each CAF subtype. Our stromal analyses uncovered two prognostically distinct myCAF regulatory states, highlighting a putative tumor-promoting myCAF subpopulation. Our work provides a high-resolution description of epigenetic cell state heterogeneity in PDAC, revealing novel regulators and gene programs associated with PDAC subtypes and clinical outcome. Kevin Hawthorne, Motoyuki Tsuda, Jennifer Eng, Patrick Worth, Brett Sheppard, Andrew Fields, Colin Daniel, Andrew Nishida, Carl Pelz, Trent Waugh, Ethan Agritelley, John Muschler, Jason Link, Andrew Adey, Rosalie C. Sears. Chromatin accessibility profiling of human pancreatic tumors reveals epigenetic features of malignant and stromal cell subtypes [abstract]. In: Proceedings of the AACR Conference on Pancreatic Cancer: New Frontiers in Biology and Therapeutic Development; 2026 Sep 25-28; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(18_Suppl_2):Abstract nr A029.