Nestin progenitor lineage is the compartment of origin for pancreatic intraepithelial neoplasia

• Published in: Proceedings of the National Academy of Sciences - PNAS 2007-03, Vol.104 (11), p.4437-4442
• Main Authors: Carrière, Catherine, Seeley, Elliott S, Goetze, Tobias, Longnecker, Daniel S, Korc, Murray
• Format: Article
• Language: English
• Subjects: Acinar cells; Animals; Biological Sciences; Carcinoma, Pancreatic Ductal - metabolism; Carcinoma, Pancreatic Ductal - pathology; Cell Lineage; Cell lines; Cellular biology; Disease Models, Animal; Endocrine cells; Endothelial cells; Exocrine cells; Gene expression; Genes, ras; Homeodomain Proteins - metabolism; Intermediate Filament Proteins - biosynthesis; Lesions; Mice; Mice, Transgenic; Models, Biological; Mutation; Nerve Tissue Proteins - biosynthesis; Nestin; Oncology; Pancreas; Pancreas - metabolism; Pancreatic cells; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - pathology; Progenitor cells; Proteins; Recombinases - metabolism; Rodents; Stem Cells - metabolism; Trans-Activators - metabolism; Tumors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.0701117104

To determine the cell compartment in which initial oncogenic mutations occur in pancreatic ductal adenocarcinoma (PDAC), we generated a mouse model in which endogenous expression of mutated Kras (KrasG¹²D) was initially directed to a population of pancreatic exocrine progenitors characterized by the expression of Nestin. Targeting of oncogenic Kras to such a restricted cell compartment was sufficient for the formation of pancreatic intraepithelial neoplasias (PanINs), putative precursors to PDAC. PanINs appeared with the same grade and frequency as observed when KrasG¹²D was targeted to the whole pancreas by a Pdx1-driven Cre recombinase strategy. Thus, the Nestin cell lineage is highly responsive to Kras oncogenic activation and may represent the elusive progenitor population in which PDAC arises.