Oncogenic KRASG12D expression induces early to advanced stage PanIN. (A) Conditional heterozygous KRASLSL-G12D allele is and generation of the expressed KRASG12D allele following Cre recombination. Samples were stained with hematoxylin and eosin. (B) Cross section of normal pancreatic tissue from a wild-type mouse revealed a flat ductal epithelium monolayer. (C) PanIN-1A lesion composed of tall columnar cells with basally-located nuclei and abundant mucin glycoprotein. (D) PanIN-1B lesion exhibiting basally pseudostratified structures, but otherwise identical to PanIN-1A. (E) PanIN-2 lesion exhibiting a marked loss of polarity and moderate nuclear atypia. (F) PanIN-3 lesion with complete loss of cellular polarity, marked nuclear atypia and cell clusters budding into the ductal lumen. (G) Pancreatic ductal adenocarcinoma exhibiting a tendency to invade adjacent structures, including islets. Scale bar, 100 µm. PanIN, pancreatic intraepithelial neoplasia; KRAS, KRAS proto-oncogene GTPase; PDX-1, pancreatic and duodenal homeobox 1.