title: The Nestin progenitor lineage is the compartment of origin for pancreatic intraepithelial neoplasia.
abstract: 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 (Kras(G12D)) 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 Kras(G12D) 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.
authors.affiliation: Department of Medicine, Dartmouth Medical School, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Hanover, NH 03756, USA. catherine.carriere@dartmouth.edu
authors.forename: Catherine
authors.initials: C
authors.lastname: Carrière
authors.forename: Elliott S
authors.initials: ES
authors.lastname: Seeley
authors.forename: Tobias
authors.initials: T
authors.lastname: Goetze
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Longnecker
authors.forename: Murray
authors.initials: M
authors.lastname: Korc
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D019070:Cell Lineage; D004195:Disease Models, Animal; D011905:Genes, ras; D018398:Homeodomain Proteins / Q000378:metabolism; D007381:Intermediate Filament Proteins / Q000096:biosynthesis*; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D064231:Nestin; D010179:Pancreas / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D045522:Recombinases / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D018398:Homeodomain Proteins; D007381:Intermediate Filament Proteins; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; D045522:Recombinases; D015534:Trans-Activators; C084010:pancreatic and duodenal homeobox 1 protein