This dissertation investigates the unknown epigenetic basis of malignant cell states in pancreatic ductal adenocarcinoma (PDAC). By profiling human PDAC tumors with single cell ATAC-seq, we delineate epigenetic cell states across tumor epithelial, stromal, and immune compartments, and uncover distinct routes of lineage reprogramming that lead to clinically unfavorable PDAC subtypes. From these results, this dissertation hypothesizes the pancreas' natural metaplasia programs as the biological foundation of PDAC cell states, and proposes a plasticity framework that links lineage reprogramming to early and late disease progression.
