Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) is a uniformly lethal neoplasm. PDAC arises in association with microscopic precursor lesions known as pancreatic intraepithelial neoplasia (PanIN). The cellular origins of PDAC remain an enigma, and despite the "ductal" moniker, studies in genetically engineered mice (GEM) have failed to definitively establish an ontogenic relationship with mature ductal epithelium. Recent GEM models of PDAC recapitulating the cognate human disease were created by developmental targeting of mutant KrasG12D to the entire pancreatic anlage, using Pdx1-regulated Cre recombination. However these elegant studies did not specifically address the cellular origins of murine PanINs (mPanINs) in the context of adult pancreata, which is the biologically relevant soil for PDAC. Methods: In order to determine the phenotypic effects of oncogenic KrasG12D in the mature pancreas, we generated Pdx1-CreERT2; LSL-KrasG12D and Elastase (Ela)-CreERT2; LSL-KrasG12D mice. Post-natally, Pdx1 expression is restricted to endocrine cells, while Ela expression is restricted to the exocrine acinar / centro-acinar population. Tamoxifen-mediated CreERT2 activation in these GEM permits targeting mutant KrasG12D to the respective Pdx1 and Ela-expressing cell types. Therefore, at 6 weeks of age, tamoxifen was administered as once daily intraperitoneal injection for a period of 5 days. Thirty mice were generated from each cohort (Pdx1-CreERT2; LSL-KrasG12D and Ela-CreERT2; LSL-KrasG12D), and groups of five mice were harvested at two-monthly intervals, beginning at 2 months post-tamoxifen injection, and culminating at 1 year. Non-induced littermates were used as control. Results: No pancreatic phenotype was observed in Pdx1-CreERT2; LSL-KrasG12D mice even at 1 year post-induction. In contrast, Ela-CreERT2; LSL-KrasG12D mice spontaneously developed mPanIN at 4 months, and by 1 year, had developed the entire histologic spectrum of pre-invasive lesions, including high-grade mPanIN-3. The advanced mPanINs typically arose in association with lobular atrophy, acinar to ductal metaplasia, and presence of intermediate acinar-ductal cell types. Conclusions: While developmental targeting of mutant KrasG12D to Pdx1-expressing cells consistently results in a pre-invasive ductal phenotype, Pdx1-expressing cells in the post-natal pancreas appear to be largely resistant to effects of the oncogenic allele. In contrast, the mature Ela-expressing acinar / centroacinar population retains its susceptibility for spontaneous mPanIN formation. A recent report by Guerra and colleagues had suggested the absolute requirement for concomitant exocrine injury (chronic pancreatitis) in order for mPanINs to develop in the context of Kras misexpression in mature exocrine tissues. However, as the Ela-CreERT2; LSL-KrasG12D mice demonstrate, the Ela-expressing acinar / centroacinar cells can be spontaneously induced along a path towards pancreatic neoplasia by a single initiating genetic event.

Talk to us

Join us for a 30 min session where you can share your feedback and ask us any queries you have

Schedule a call

Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.