Molecular subtyping of cancer offers tremendous promise for the optimization of 
a precision oncology approach to anticancer therapy. Recent advances in 
pancreatic cancer research uncovered various molecular subtypes with tumors 
expressing a squamous/basal-like gene expression signature displaying a worse 
prognosis. Through unbiased epigenome mapping, we identified deltaNp63 as a 
major driver of a gene signature in pancreatic cancer cell lines, which we 
report to faithfully represent the highly aggressive pancreatic squamous subtype 
observed in vivo, and display the specific epigenetic marking of genes 
associated with decreased survival. Importantly, depletion of deltaNp63 in these 
systems significantly decreased cell proliferation and gene expression patterns 
associated with a squamous subtype and transcriptionally mimicked a subtype 
switch. Using genomic localization data of deltaNp63 in pancreatic cancer cell 
lines coupled with epigenome mapping data from patient-derived xenografts, we 
uncovered that deltaNp63 mainly exerts its effects by activating 
subtype-specific super enhancers. Furthermore, we identified a group of 45 
subtype-specific super enhancers that are associated with poorer prognosis and 
are highly dependent on deltaNp63. Genes associated with these enhancers 
included a network of transcription factors, including HIF1A, BHLHE40, and RXRA, 
which form a highly intertwined transcriptional regulatory network with 
deltaNp63 to further activate downstream genes associated with poor survival.