Pancreatic ductal adenocarcinoma (PDAC) remains one of the most devastating human diseases. There is consequently a pressing need to understand its molecular underpinnings, which should enable new preventive and therapeutic strategies. A new study in The EMBO Journal (Diaferia et al, 2016) maps the transcriptome and epigenetic landscape associated with distinct PDAC grades and identifies cis‐ and trans‐regulatory elements in tumour progression.
See also: GR Diaferia et al (March 2016)
PDAC originally acquired its name from its histological similarity with normal pancreatic ducts. However, recent work has shown that tumours with ductal morphology can arise upon activation of mutant Kras in duct‐like embryonic pancreatic progenitors or in pancreatic acinar cells through a process known as acino‐ductal metaplasia (Tuveson et al, 2004; Guerra et al, 2007; Pérez‐Mancera et al, 2012). Acino‐ductal metaplasia has thus been proposed to involve a process where acinar cells are reprogrammed to an embryonic duct cell progenitor state (Rooman & Real, 2012; Roy & Hebrok, 2015). PDAC tumours of low or moderate histological grade retain ductal features, while this phenotype is not seen in more aggressive high‐grade tumours. The profound changes in cellular phenotypes that take place throughout pancreatic carcinogenesis are likely triggered by both somatic genetic alterations in tumour cells and environmental cues such as stromal‐derived signals, but they need to be executed by cell‐specific transcriptional programmes. This means that there should be specific transcription factors that control regulatory programmes in each histological phenotype. …
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