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PLoS One. 2017 Sep 21;12(9):e0184984. doi: 10.1371/journal.pone.0184984. eCollection 2017.

Generation of a pancreatic cancer model using a Pdx1-Flp recombinase knock-in allele.

Author information

1
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, United States of America.
2
Cancer Biology and Genetics Department, The Ohio State University, Columbus, Ohio, United States of America.
3
Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, United States of America.
4
Hollings Cancer Center, Medical University of South Carolina, Charleston, South Carolina, United States of America.
5
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, United States of America.

Abstract

The contribution of the tumor microenvironment to the development of pancreatic adenocarcinoma (PDAC) is unclear. The LSL-KrasG12D/+;LSL-p53R172H/+;Pdx-1-Cre (KPC) tumor model, which is widely utilized to faithfully recapitulate human pancreatic cancer, depends on Cre-mediated recombination in the epithelial lineage to drive tumorigenesis. Therefore, specific Cre-loxP recombination in stromal cells cannot be applied in this model, limiting the in vivo investigation of stromal genetics in tumor initiation and progression. To address this issue, we generated a new Pdx1FlpO knock-in mouse line, which represents the first mouse model to physiologically express FlpO recombinase in pancreatic epithelial cells. This mouse specifically recombines Frt loci in pancreatic epithelial cells, including acinar, ductal, and islet cells. When combined with the Frt-STOP-Frt KrasG12D and p53Frt mouse lines, simultaneous Pdx1FlpO activation of mutant Kras and deletion of p53 results in the spectrum of pathologic changes seen in PDAC, including PanIN lesions and ductal carcinoma. Combination of this KPF mouse model with any stroma-specific Cre can be used to conditionally modify target genes of interest. This will provide an excellent in vivo tool to study the roles of genes in different cell types and multiple cell compartments within the pancreatic tumor microenvironment.

PMID:
28934293
PMCID:
PMC5608307
DOI:
10.1371/journal.pone.0184984
[Indexed for MEDLINE]
Free PMC Article

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