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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 …
Contributors GRD wrote the manuscript with contributions from GN. Funding acquisition was obtained by GRD and GN.
Funding Research in this area is supported by the Italian Association for Research on Cancer (A.I.R.C. investigator grant 20 251 to GN and AIRC 5×1000 Grant ISM) and by the Italian Ministry of Health (grant GR-2016-02361721 to GRD).
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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