Genetically Engineered Mouse Models of Pancreatic Ductal Adenocarcinoma

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death in the United States. While the incidence of PDAC is low ­compared to that of the more common malignancies such as lung, breast, prostate, and colon cancer, it is the disease’s lethality – nearly all patients who develop the disease die from it – which makes it a significant health menace. PDAC is ­characterized by spread to other organs early in the course of disease and a general resistance to chemotherapy. Insight into the molecular pathogenesis of PDAC has come from analysis of the pathologic precursor lesions found adjacent to cancers in resected cases. The identification of KRAS , INK4A , P53 , and SMAD4 mutations in these precursor lesions and advanced PDAC has provided the genetic framework for recent efforts to model the disease. The current models offer valuable tools for the study of PDAC and have been used to investigate critical signaling networks, stromal epithelial interactions, and potential cells of origin and early stages of disease [Hezel et al. Genes Dev. 20:1218–49, 2006]. In this chapter we review the development of genetically engineered mouse models (GEMMs) of PDAC and discuss how such models have given insight into disease biology and provided a foundation for preclinical testing. We also discuss emerging improvements in the PDAC models and how these will impact both basic and therapeutic research in the future.