Emerging insights into lineage plasticity in pancreatic cancer initiation, progression, and therapy resistance.

Lineage plasticity, the ability of cells to switch from one specialized identity to another, is a fundamental cellular process in embryonic development and tissue regeneration. The process is often hijacked by tumor cells at various stages to facilitate cancer initiation, progression, metastasis, and therapy resistance. It is also recognized as a key contributor to intratumor heterogeneity (ITH). In pancreatic ductal adenocarcinoma (PDAC), lineage plasticity is central to acinar-to-ductal metaplasia (ADM) and its associated acinar-to-ductal reprogramming (ADR), epithelial-mesenchymal transition (EMT), cancer stem cell (CSC) regeneration, and molecular subtype rewiring. These mechanisms generate diverse lineage trajectories that shape PDAC development, progression, and therapeutic outcomes. In this review, we discuss how normal and tumor cells in the pancreatic epithelium acquire lineage plasticity and its implications for PDAC pathogenesis, ITH, metastasis, and therapy resistance. We also highlight recent discoveries suggesting potential therapeutic strategies targeting key regulators of lineage plasticity in PDAC.