Understanding the heterogeneity of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive, treatment-resistant cancer characterized by extensive inter- and intra-tumoral heterogeneity. Although over 95 % of cases harbor KRAS mutations and commonly altered tumor suppressors like TP53, SMAD4, and CDKN2A, these genetic changes alone do not fully explain PDAC variability. We propose a paradigm shift: PDAC heterogeneity is not solely genetic but also shaped by epigenetic regulation and the tumor microenvironment. Traditional transcriptomic classifications define PDAC into fixed subtypes, primarily classical and basal-like, but we argue these are not static categories. Instead, PDAC phenotypes exist along a dynamic continuum influenced by stromal interactions and epigenetic cues. This model challenges the binary classification view. We show that transitions from classical to basal-like states are gradual and reversible, driven by tumor-stroma crosstalk and chromatin remodeling. Such plasticity underpins tumor adaptation, resistance, and progression. Embracing this dynamic framework offers novel therapeutic opportunities.