An Epigenetetic Signature for Classifying Pancreatic Ductal Adenocarcinoma Based on their Cellular Origin

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, characterized by significant heterogeneity that complicates treatment and diagnosis. While acinar and ductal cells can serve as the origins of PDAC in mice, shaping differently tumor biology, no practical method exists to predict the cell of origin in PDAC models. Here, we leveraged DNA methylation as a powerful tool to trace the cellular origins of PDAC. We identified a cell-of-origin DNA methylation signature comprising 178 CpG sites. This signature remains preserved during tumorigenesis and robustly differentiates acinar-origin from ductal-origin PDAC samples across different experimental settings. It also predicted the cell of origin of PDAC samples from KPC mice, the most commonly used preclinical PDAC model, and revealed the influence of oncogenic mutations on tumor fate. A logistic regression model further confirmed the origin of most tumor samples. Notably, cell of origin influences PDAC characteristics and treatment response, underscoring its potential role in patient stratification, origin-informed molecular subtyping, and development of novel therapies. Our findings also raise important questions about the relevance of KPC mice as a preclinical model and the mechanisms driving PDAC heterogeneity.

ORGANISM(S): Mus musculus

PROVIDER: GSE290346 | GEO | 2026/02/24

REPOSITORIES: GEO