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Pancreatic ductal adenocarcinoma (PDAC) represents approximately 90% of all malignant tumours in the pancreas, and it is one of the deadliest human diseases. It has a 5-year survival rate of less than 10%, primarily due to the lack of early symptoms and of effective therapies. With its rising incidence, PDAC is projected to become the second leading cause of cancer-related deaths in the Western world by 2030.1 PDAC can be stratified into two main distinct molecular subtypes, classical and basal, exhibiting distinct clinical characteristics: the classical subtype is associated with better prognosis and a less aggressive clinical course, while the basal subtype associates with worse prognosis and higher resistance to therapy. The transcription factors GATA6 and ΔNp63 play pivotal roles in regulating these identities,2 3 GATA6 being associated with the classical phenotype while ΔNp63 is linked to the basal phenotype. These cellular profiles are driven by distinct epigenetic programmes involving subtype-specific enhancers and transcriptional configurations, which dictate the distinct molecular landscapes of each transcriptomic class. The cellular plasticity of PDAC cells and transitions between subtypes are important for driving aggressiveness in PDAC.4 5 Understanding the mechanisms behind these regulatory networks is crucial for developing targeted therapies and improving patient outcomes in PDAC.