Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal malignancies, with limited therapeutic success and a persistently low 5-year survival rate. Despite significant advances in genomics and tumor biology, a fundamental challenge persists: to identify the elusive transformation from common benign pancreatic lesions to occasional malignant cellular identity. This review addresses a critical missing link in PDAC pathogenesis, focusing on when and where the switch to malignancy occurs, and why surgical intervention is often insufficient. We explore the biological and spatial-temporal evolution of precancerous lesions, such as PanINs and IPMNs, and examine how phenotypic plasticity and overlapping cellular programs-including squamous transdifferentiation, epithelial-to-mesenchymal transition (EMT), and acquisition of mesenchymal features-contribute to early dissemination, treatment resistance, and surgical failure. Recognizing and characterizing these early molecular events is essential for rethinking therapeutic strategies, identifying actionable biomarkers, and redefining the temporal window when curative intervention is feasible.