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Generation of a pancreatic cancer model using a Pdx1-Flp recombinase knock-in allele.
- Source :
-
PloS one [PLoS One] 2017 Sep 21; Vol. 12 (9), pp. e0184984. Date of Electronic Publication: 2017 Sep 21 (Print Publication: 2017). - Publication Year :
- 2017
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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.
- Subjects :
- Animals
Cell Transformation, Neoplastic genetics
Cell Transformation, Neoplastic metabolism
DNA Nucleotidyltransferases genetics
Disease Progression
Female
Male
Mice
Mice, Inbred C57BL
Pancreatic Neoplasms genetics
Pancreatic Neoplasms metabolism
Proto-Oncogene Proteins p21(ras) genetics
Signal Transduction
Tumor Microenvironment
Tumor Suppressor Protein p53 genetics
Cell Transformation, Neoplastic pathology
DNA Nucleotidyltransferases metabolism
Disease Models, Animal
Homeodomain Proteins physiology
Pancreatic Neoplasms pathology
Trans-Activators physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1932-6203
- Volume :
- 12
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- PloS one
- Publication Type :
- Academic Journal
- Accession number :
- 28934293
- Full Text :
- https://doi.org/10.1371/journal.pone.0184984