ZFIN ID: ZDB-PUB-080616-22
Oncogenic KRAS Induces Progenitor Cell Expansion and Malignant Transformation in Zebrafish Exocrine Pancreas
Park, S.W., Davison, J.M., Rhee, J., Hruban, R.H., Maitra, A., and Leach, S.D.
Date: 2008
Source: Gastroenterology   134(7): 2080-2090 (Journal)
Registered Authors: Leach, Steven D.
Keywords: none
MeSH Terms:
  • Animals
  • Animals, Genetically Modified
  • Cell Differentiation
  • Cell Movement
  • Cell Proliferation*
  • Cell Transformation, Neoplastic/genetics
  • Cell Transformation, Neoplastic/metabolism*
  • Cell Transformation, Neoplastic/pathology
  • Chromosomes, Artificial, Bacterial
  • Gene Expression Regulation, Neoplastic*
  • Genotype
  • Green Fluorescent Proteins/metabolism
  • Hedgehog Proteins/metabolism
  • Humans
  • Microscopy, Fluorescence
  • Neoplasm Invasiveness
  • Neoplasms, Experimental/genetics
  • Neoplasms, Experimental/metabolism
  • Neoplasms, Experimental/pathology
  • Neoplastic Stem Cells/metabolism*
  • Neoplastic Stem Cells/pathology
  • Pancreas, Exocrine/metabolism*
  • Pancreas, Exocrine/pathology
  • Pancreatic Neoplasms/enzymology
  • Pancreatic Neoplasms/genetics
  • Pancreatic Neoplasms/metabolism*
  • Pancreatic Neoplasms/pathology
  • Phenotype
  • Proto-Oncogene Proteins/genetics
  • Proto-Oncogene Proteins/metabolism*
  • Recombinant Fusion Proteins/metabolism
  • Signal Transduction
  • Time Factors
  • Transcription Factors/genetics
  • Zebrafish/genetics
  • Zebrafish/metabolism*
  • ras Proteins/genetics
  • ras Proteins/metabolism*
PubMed: 18549880 Full text @ Gastroenterology
Background & Aims: Although the cell of origin for pancreatic cancer remains unknown, prior studies have suggested that pancreatic neoplasia may be initiated in progenitor-like cells. To examine the effects of oncogene activation within the pancreatic progenitor pool, we devised a system for real-time visualization of both normal and oncogenic KRAS-expressing pancreatic progenitor cells in living zebrafish embryos. Methods: By using BAC transgenes under the regulation of ptf1a regulatory elements, we expressed either extended green fluorescent protein (eGFP) alone or eGFP fused to oncogenic KRAS in developing zebrafish pancreas. Results: After their initial specification, normal eGFP-labeled pancreatic progenitor cells were observed to actively migrate away from the forming endodermal gut tube, and subsequently underwent characteristic exocrine differentiation. In contrast, pancreatic progenitor cells expressing oncogenic KRAS underwent normal specification and migration, but failed to differentiate. This block in differentiation resulted in the abnormal persistence of an undifferentiated progenitor pool, and was associated with the subsequent formation of invasive pancreatic cancer. These tumors showed several features in common with the human disease, including evidence of abnormal Hedgehog pathway activation. Conclusions: These results provide a unique view of the tumor-initiating effects of oncogenic KRAS in a living vertebrate organism, and suggest that zebrafish models of pancreatic cancer may prove useful in advancing our understanding of the human disease.