Generation of a pancreatic cancer model using a Pdx1-Flp recombinase knock-in allele. PLoS One 2017;12(9):e0184984
Date
09/22/2017Pubmed ID
28934293Pubmed Central ID
PMC5608307DOI
10.1371/journal.pone.0184984Scopus ID
2-s2.0-85029768561 (requires institutional sign-in at Scopus site) 14 CitationsAbstract
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.
Author List
Wu J, Liu X, Nayak SG, Pitarresi JR, CuitiƱo MC, Yu L, Hildreth BE 3rd, Thies KA, Schilling DJ, Fernandez SA, Leone G, Ostrowski MCAuthor
Gustavo Leone PhD Sr Associate Dean, Director, Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCell Transformation, Neoplastic
DNA Nucleotidyltransferases
Disease Models, Animal
Disease Progression
Female
Homeodomain Proteins
Male
Mice
Mice, Inbred C57BL
Pancreatic Neoplasms
Proto-Oncogene Proteins p21(ras)
Signal Transduction
Trans-Activators
Tumor Microenvironment
Tumor Suppressor Protein p53