Ductal pancreatic cancer in humans and mice

Abstract

Pancreatic ductal adenocarcinoma (PDA) eludes early detection and resists current therapies, earning its distinction as the most lethal malignancy by organ site in the western world. This dire reality prompted extensive yet generally disappointing efforts to generate transgenic mouse models of this malignancy. Recently, mutant mice that develop pancreatic intraepithelial neoplasms (PanIN), the presumed preinvasive stage of PDA, were produced by conditionally expressing an endogenous oncogenic Kras allele in the developing murine pancreas. Mice with PanIN demonstrated promise in the pursuit of biomarkers of early pancreatic cancer, and, importantly, such mice eventually developed and succumbed to PDA after a long latency, establishing PanINs as true precursors to the invasive disease. Furthermore, the incorporation of conditional mutations in tumor suppressor alleles known to be altered in human PDA synergized with oncogenic Kras to produce advanced PDA with a short latency, recapitulating central pathophysiological events in human PDA. These models facilitate a variety of biological and clinical investigations such as explorations of the cellular origins of PDA and the development of treatment strategies for advanced PanIN and PDA. In addition, lessons from modeling PDA may be applicable to other tumor types and illuminate general principles of carcinogenesis.