Epigenetic progression of pancreatic cancer to aggressive subtypes involves alternate routes of lineage reprogramming in subtype-intermediate progenitor cells

Pancreatic ductal adenocarcinoma (PDAC) arises from a complex plasticity of malignant cells, with epigenetic alterations playing a significant role. However, the underlying regulatory landscape remains poorly understood. To shed light on this, researchers analyzed 33 primary tumors and 7 metastases from 39 PDAC patients using single-cell ATAC-seq and RNA-seq profiles.

They identified a classical-basal subtype-intermediate progenitor state (SIP) characterized by co-accessibility of GATA6 and KRT17, which is associated with better clinical outcomes. Cells in this state show limited epigenetic reprogramming from premalignant epithelium and maintain gastric-intestinal differentiation, akin to neoplastic precursors. In contrast, lineages lacking this co-accessibility exhibit increased lineage and epithelial-mesenchymal plasticity.

Classical PDACs that suppress basal gene accessibility activate neural-like progenitor (NRP) and tuft lineage enhancers, while basal committed tumors display evidence of esophageal transdifferentiation. Compared to SIP, classical-NRP and basal committed tumors have poorer prognoses and display distinct PD-1/PD-L1 immune proteomic phenotypes and myofibroblast epigenetic states, respectively.

The study highlights the intricate connections between lineage reprogramming, epithelial-mesenchymal transition (EMT), and epigenetic progression in human PDAC. These findings provide valuable insights into the progression of PDAC and may guide future therapeutic strategies targeting these specific lineages.