The Nestin progenitor lineage is the compartment of origin for pancreatic intraepithelial neoplasia.
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.
Carrière
Catherine
C
Department of Medicine, Dartmouth Medical School, Dartmouth Hitchcock Medical Center, One Medical Center Drive, Hanover, NH 03756, USA. catherine.carriere@dartmouth.edu
Seeley
Elliott S
ES
Goetze
Tobias
T
Longnecker
Daniel S
DS
Korc
Murray
M
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
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