Figure 1 from KRAS Loss of Heterozygosity Promotes MAPK-Dependent Pancreatic Ductal Adenocarcinoma Initiation and Induces Therapeutic Sensitivity to MEK Inhibition
Loss of WT Kras increases PanIN formation in the presence of oncogenic Kras. A, Kaplan–Meier survival curve for human patients with PDAC with KRAS alleles balanced and KRAS alleles imbalanced. KRAS balanced, n = 47; KRAS imbalanced, n = 32. *, P = 0.029, log-rank (Mantel–Cox) test. B, Proportion of human patients with pancreatic cancer with KRAS alleles balanced (59.5%) and KRAS alleles imbalanced (40.5%), from A. C, Schematic representing generation of KC KrasG12D/fl mice. D, Representative hematoxylin and eosin (H&E) images of pancreata from KC KrasG12D/+ and KC KrasG12D/fl mice at 42 days of age, representative of six mice per group. Scale bar, 200 μm. E, Quantification and grading of PanINs from KC KrasG12D/+ and KC KrasG12D/fl mice at 42 days of age from one whole hematoxylin and eosin section per mouse (n = 6 per group), represented by D. Boxes depict the IQR, the central line indicates the median, and whiskers indicate minimum/maximum values. **, P < 0.01; one-way Mann–Whitney U test. F, Quantification of the area of ADM per mm2 pancreas over one whole hematoxylin and eosin section from KC KrasG12D/+ and KC KrasG12D/fl mice at 42 days of age (n = 6 per group). Boxes depict the IQR, the central line indicates the median, and whiskers indicate minimum/maximum values. **, P < 0.0011; one-way Mann–Whitney U test. G, Left, representative IHC images of pERK1/2 of pancreata from KC KrasG12D/+ and KC KrasG12D/fl mice at 42 days of age. Representative of six mice per group. Scale bar, 200 μm. Right, bar graphs showing quantification of pERK1/2-positive cells of the pancreatic epithelium of KC KrasG12D/+ and KC KrasG12D/fl mice sampled at day 42 (KC KrasG12D/+, n = 6; KC KrasG12D/fl, n = 6). Data are the mean ± SEM. *, P = 0.0325; one-way Mann–Whitney U test. H, Left, representative images of ISH of Dusp5 and Dusp6 of pancreata from KC KrasG12D/+ and KC KrasG12D/fl mice at 42 days of age. Representative of six mice per group. Scale bar, 200 μm. Right, quantification of Dusp5 and Dusp6 ISH staining of pancreatic lesions (PanINs) of pancreata from KC KrasG12D/+ and KC KrasG12D/fl mice at 42 days of age (KC KrasG12D/+, n = 6; KC KrasG12D/fl, n = 6). Data are the mean ± SEM. **, P = 0.0011 (Dusp5); **, P = 0.0022 (Dusp6); one-way Mann–Whitney U test. Cre, Cre recombinase; loxP, Cre-loxP recombination site.