EZH2 deletion does not impact acinar regeneration but restricts progression to pancreatic cancer in mice.

Enhancer of Zeste Homologue 2 (EZH2) is part of the Polycomb Repressor Complex 2, which promotes trimethylation of lysine 27 on histone 3 (H3K27me3) and genes repression. EZH2 is overexpressed in many cancers and studies in mice attributed both pro-oncogenic and tumor suppressive functions to EZH2 in pancreatic ductal adenocarcinoma (PDAC). EZH2 deletion enhances de novo KRAS-driven neoplasia following pancreatic injury, while increased EZH2 expression in PDAC patients is correlated to poor prognosis, suggesting a context-dependant effect for EZH2 in PDAC progression.

Mouse Models for Pancreatic Ductal Adenocarcinoma are Affected by the cre-driver Used to Promote KRAS Activation.

Background & Aims: The fundamental biology of pancreatic ductal adenocarcinoma has been greatly impacted by the characterization of genetically engineered mouse models that allow temporal and spatial activation of oncogenic KRAS (KRAS). One of the most commonly used models involves targeted insertion of a cre-recombinase into the Ptf1a gene. However, this approach disrupts the Ptf1a gene, resulting in haploinsufficiency that likely affects sensitivity to oncogenic KRAS (KRAS).

The unfolded protein response: An emerging therapeutic target for pancreatitis and pancreatic ductal adenocarcinoma.

Pancreatitis is a debilitating disease involving inflammation and fibrosis of the exocrine pancreas. Recurrent or chronic forms of pancreatitis are a significant risk factor for pancreatic ductal adenocarcinoma. While genetic factors have been identified for both pathologies, environmental stresses play a large role in their etiology.

Loss of activating transcription factor 3 prevents KRAS-mediated pancreatic cancer.

The unfolded protein response (UPR) is activated in pancreatic pathologies and suggested as a target for therapeutic intervention. In this study, we examined activating transcription factor 3 (ATF3), a mediator of the UPR that promotes acinar-to-ductal metaplasia (ADM) in response to pancreatic injury. Since ADM is an initial step in the progression to pancreatic ductal adenocarcinoma (PDAC), we hypothesized that ATF3 is required for initiation and progression of PDAC.