Open AccessGeneration of a pancreatic cancer model using a Pdx1-Flp recombinase knock-in allele
Author(s) -
Jinghai Wu,
Xin Liu,
Sunayana G. Nayak,
Jason R. Pitarresi,
Maria C. Cuitiño,
Lianbo Yu,
Blake E. Hildreth,
Katie Thies,
Daniel J. Schilling,
Soledad Fernández,
Gustavo Leone,
Michael C. Ostrowski
Publication year - 2017
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0184984
Subject(s) - cre recombinase , pancreatic cancer , biology , stromal cell , pancreatic intraepithelial neoplasia , cancer research , pdx1 , carcinogenesis , kras , tumor microenvironment , mutation , cancer , genetics , gene , transgene , genetically modified mouse , pancreatic ductal adenocarcinoma , tumor cells , transcription factor
The contribution of the tumor microenvironment to the development of pancreatic adenocarcinoma (PDAC) is unclear. The LSL-Kras G12D/+ ; LSL-p53 R172H/+ ; 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 Kras G12D and p53 Frt 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.