Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 104, Issue 11, Pages 4437-4442Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0701117104
Keywords
pancreatic ductal adenocarcinoma; cell of origin; Kras(G12D)
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Funding
- NCI NIH HHS [CA 75059, R01 CA075059, R37 CA075059, R01 CA102687, CA 102687] Funding Source: Medline
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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 intra-epithelial 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.
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