What We Have Learned About Pancreatic Cancer From Mouse Models Pedro A. Pérez–Mancera, Carmen Guerra, Mariano Barbacid, David A. Tuveson  Gastroenterology  Volume 142, Issue 5, Pages 1079-1092 (May 2012) DOI: 10.1053/j.gastro.2012.03.002 Copyright © 2012 AGA Institute Terms and Conditions

Figure 1 PanIN to PDA GEMMs. Expression of Cre recombinase, regulated by pancreas-specific promoters (PSP), leads to conditional activation of endogenous mutant alleles of Kras in the pancreas compartment; these induce development of PanINs. PanINs can progress to frank malignancy in cooperation with loss of tumor suppressor genes, including p53, p16Ink4a/p19Arf, Smad4, and Tgfbr2. Nongenetic events, such as induction of pancreatitis by cerulein, cooperate with oncogenic Kras in PanINs to promote progression to PDA. Arrow, PanIN; star, acinar compartment; triangle, islet. Gastroenterology 2012 142, 1079-1092DOI: (10.1053/j.gastro.2012.03.002) Copyright © 2012 AGA Institute Terms and Conditions

Figure 2 GEMMs that combine the Cre/loxP and FLP/FRT systems to probe either the microenvironment or neoplastic cells. (A) Schematic representation of the generation of GEMMs to study the contribution of the stroma in progression of PDA. In this model, a pancreas-specific promoter (PSP) directs expression of the Cre recombinase in pancreatic cells to result in removal of the transcriptional stop (STOP) cassette flanked by loxP sites (green circles) and activating expression of oncogenic Kras in ductal cells. Simultaneously, a stroma-specific promoter (SSP) directs the expression of the FLP recombinase; removal of the genomic sequences flanked by FRT sites (gray diamonds) inactivates the gene of interest (GOI) in the stroma compartment. (B) Schematic representation of the generation of GEMMs to study the cooperation between oncogenic Kras and tumor suppressor genes in progression of PanINs to PDA. In this model, a PSP induces the expression of the FLP recombinase; removal of the STOP cassette flanked by FRT sites (gray diamonds) upstream of the Kras exon 1 directs expression of oncogenic Kras and a Cre-ERT2 recombinase allele, controlled by the Rosa26 promoter, in ductal cells. The activation of Cre recombinase after administration of tamoxifen conditionally deletes expression of the GOI in the cell-autonomous compartment. FSF, FRT-STOP-FRT cassette. Gastroenterology 2012 142, 1079-1092DOI: (10.1053/j.gastro.2012.03.002) Copyright © 2012 AGA Institute Terms and Conditions

Figure 3 Forward genetic screens for genes that contribute to PDA. (A) The T2/Onc transposon91 contains bidirectional polyadenylation sequences to trap upstream exons and inactivate potential tumor suppressor genes (TSGs) (loss-of-function activity) and the mouse stem cell virus (MSCV) promoter to activate potential proto-oncogenes or dominant-negative forms of TSGs downstream of the integration site (gain-of-function activity). (B) The conditional expression of the SB transposase with the Pdx1-Cre allele induces the mobilization of the T2/Onc transposon from the donor concatemer, producing a progression of PDA. Gastroenterology 2012 142, 1079-1092DOI: (10.1053/j.gastro.2012.03.002) Copyright © 2012 AGA Institute Terms and Conditions

Figure 4 Imaging pancreatic tumors in GEMMs of PDA. (A) Image of in situ PDA (dotted lines) by high-resolution ultrasonography. (B) FDG-PET and CT images of a pancreatic tumor (dotted lines) developed in a Pdx1-Cre; LSL-KrasG12D; LSL-p53R172H mouse. FDG-PET uses the glucose analogue FDG to detect increased levels of glucose consumption by the tumor cells. Gastroenterology 2012 142, 1079-1092DOI: (10.1053/j.gastro.2012.03.002) Copyright © 2012 AGA Institute Terms and Conditions

Figure 5 Human ductal pancreatic tumors are hypovascular. Human normal pancreas and PDA stained with H&E (upper panels) and stained for CD31 (lower panels, arrows) show the hypovascular phenotype of tumors compared with normal pancreas tissue. Reprinted in part with permission from Olive et al.102 Gastroenterology 2012 142, 1079-1092DOI: (10.1053/j.gastro.2012.03.002) Copyright © 2012 AGA Institute Terms and Conditions