Abstract
To evaluate the role of oncogenic RAS mutations in pancreatic tumorigenesis, we directed endogenous expression of KRAS(G12D) to progenitor cells of the mouse pancreas. We find that physiological levels of Kras(G12D) induce ductal lesions that recapitulate the full spectrum of human pancreatic intraepithelial neoplasias (PanINs), putative precursors to invasive pancreatic cancer. The PanINs are highly proliferative, show evidence of histological progression, and activate signaling pathways normally quiescent in ductal epithelium, suggesting potential therapeutic and chemopreventive targets for the cognate human condition. At low frequency, these lesions also progress spontaneously to invasive and metastatic adenocarcinomas, establishing PanINs as definitive precursors to the invasive disease. Finally, mice with PanINs have an identifiable serum proteomic signature, suggesting a means of detecting the preinvasive state in patients.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors
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Carcinoma, Pancreatic Ductal / genetics*
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Carcinoma, Pancreatic Ductal / metabolism
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Cyclooxygenase 2
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Genes, ras / physiology*
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Homeodomain Proteins / metabolism
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Humans
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Immunohistochemistry
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Isoenzymes / metabolism
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Matrix Metalloproteinase 7 / metabolism
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Membrane Proteins
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Mice
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Mutation*
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Neoplasm Metastasis
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Neoplasm Staging
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Pancreas / metabolism
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Pancreas / pathology
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Pancreatic Neoplasms / genetics*
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Pancreatic Neoplasms / metabolism
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Prostaglandin-Endoperoxide Synthases / metabolism
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Transcription Factor HES-1
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Hes1 protein, mouse
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Homeodomain Proteins
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Isoenzymes
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Membrane Proteins
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Transcription Factor HES-1
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HES1 protein, human
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Cyclooxygenase 2
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PTGS2 protein, human
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Prostaglandin-Endoperoxide Synthases
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Matrix Metalloproteinase 7