Figure 2.

Mouse Models of Pancreatic Ductal Adenocarcinoma (PDAC) Replicate Human Pathology. To activate cancer-causing alleles specifically within the mouse pancreatic epithelium, Cre recombinase is expressed under the control of the Pdx1 or Ptf1a/p48 promoter, both of which are active in embryonic pancreatic progenitor cells. In the ‘KC’ (Kras/Cre) model, one copy of the endogenous Kras allele is mutated to change amino acid 12 from glycine to aspartic acid, locking the Kras protein in its GTP-bound (active) form. A loxP–STOP–loxP cassette (LSL) is placed upstream of this mutation and, before recombination, inhibits transcription of the mutant allele. When Cre is expressed it excises the STOP cassette, activating Kras^G12D in all epithelial cells of the early pancreas. This produces fully-penetrant pancreatic intraepithelial neoplasia (PanIN) formation, rare intraductal papillary mucinous neoplasia (IPMN) formation, and occasional PDAC (in ~50% of aged animals). In the ‘KPC’ (Kras/p53/Cre) model of invasive PDAC, the same oncogenic Kras allele is activated along with a Trp53 ‘gain-of-function’ (neomorphic) allele. The R172H point mutation in this Trp53 allele models a mutation frequently found in human PDAC. Expression of both Kras^G12D and p53^R172H using Pdx1–Cre results in fully-penetrant PanIN and PDAC development in young animals.