• pancreatic cancer
• gene regulation
• epithelial differentiation

In the last decade, many efforts have been dedicated to study pancreatic ductal adenocarcinoma (PDAC) biology to better understand the molecular bases of the aggressive clinical course and the therapeutic challenges posed by this nearly invariably lethal disease. Genetic and transcriptional studies have revealed an extensive heterogeneity that ultimately resulted in a new clinically applicable molecular taxonomy for PDAC.1 Defining PDAC subgroups with distinct subtype-specific vulnerabilities represents one of the most urgent needs required to implement tumour-targeted therapeutic strategies that may improve disease outcome.

How transcriptional heterogeneity in PDAC is determined or regulated remains unknown to a large extent, and the relative role of intrinsic and microenvironment-derived cues is unclear. At this time, PDACs can be classified into two or more major subtypes among which the ‘classical/pancreatic progenitor’ and ‘basal-like/squamous’ subtypes were validated across different platforms by integrating mutational and transcriptional profiles together with tumour purity estimates.2 These subtypes greatly overlap with histological tumour grading in that the ‘classical’ subtype corresponds to low-grade (namely, well-differentiated) tumour areas and the ‘basal-like’ to high-grade (namely, poorly differentiated) regions with squamoid features. It is important to stress that the extent to which these two differentiation grades coexist in PDACs is still unclear, suggesting that …