Understanding the heterogeneity of pancreatic ductal adenocarcinoma

• PDAC is highly heterogeneous and treatment-resistant , with tumor variability that cannot be fully explained by common genetic mutations such as KRAS, TP53, SMAD4 , and CDKN2A . • A paradigm shift is proposed : PDAC heterogeneity is driven not only by genetics but also by epigenetic regulation and the tumor microenvironment . • Traditional transcriptomic classifications (classical vs. basal-like) are inadequate , as PDAC phenotypes exist along a dynamic and reversible continuum , rather than fixed subtypes. • Transitions between classical and basal-like states are gradual , regulated by tumor-stroma crosstalk and chromatin remodeling , highlighting the plasticity of PDAC. • This dynamic framework opens new therapeutic opportunities by targeting tumor plasticity and microenvironmental interactions to overcome treatment resistance. 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.