Pancreatic cancer is almost invariably associated with mutations in the KRAS 
gene, most commonly KRASG12D, that result in a dominant-active form of the KRAS 
GTPase. However, how KRAS mutations promote pancreatic carcinogenesis is not 
fully understood, and whether oncogenic KRAS is required for the maintenance of 
pancreatic cancer has not been established. To address these questions, we 
generated two mouse models of pancreatic tumorigenesis: mice transgenic for 
inducible KrasG12D, which allows for inducible, pancreas-specific, and 
reversible expression of the oncogenic KrasG12D, with or without inactivation of 
one allele of the tumor suppressor gene p53. Here, we report that, early in 
tumorigenesis, induction of oncogenic KrasG12D reversibly altered normal 
epithelial differentiation following tissue damage, leading to precancerous 
lesions. Inactivation of KrasG12D in established precursor lesions and during 
progression to cancer led to regression of the lesions, indicating that KrasG12D 
was required for tumor cell survival. Strikingly, during all stages of 
carcinogenesis, KrasG12D upregulated Hedgehog signaling, inflammatory pathways, 
and several pathways known to mediate paracrine interactions between epithelial 
cells and their surrounding microenvironment, thus promoting formation and 
maintenance of the fibroinflammatory stroma that plays a pivotal role in 
pancreatic cancer. Our data establish that epithelial KrasG12D influences 
multiple cell types to drive pancreatic tumorigenesis and is essential for tumor 
maintenance. They also strongly support the notion that inhibiting KrasG12D, or 
its downstream effectors, could provide a new approach for the treatment of 
pancreatic cancer.