Oncogenic KRAS induces progenitor cell expansion and malignant transformation in zebrafish exocrine pancreas.

Abstract:

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.

journal_name

Gastroenterology

journal_title

Gastroenterology

authors

Park SW,Davison JM,Rhee J,Hruban RH,Maitra A,Leach SD

doi

10.1053/j.gastro.2008.02.084

subject

Has Abstract

pub_date

2008-06-01 00:00:00

pages

2080-90

issue

7

eissn

0016-5085

issn

1528-0012

pii

S0016-5085(08)00419-8

journal_volume

134

pub_type

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