Cross-Species Array Comparative Genomic Hybridization Identifies Novel Oncogenic Events in Zebrafish and Human Embryonal Rhabdomyosarcoma
Date
2013-08-29
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Publisher
PLoS Genetics, Public Library of Science
Abstract
Human cancer genomes are highly complex, making it challenging to identify specific drivers of cancer growth,
progression, and tumor maintenance. To bypass this obstacle, we have applied array comparative genomic hybridization
(array CGH) to zebrafish embryonal rhabdomyosaroma (ERMS) and utilized cross-species comparison to rapidly identify
genomic copy number aberrations and novel candidate oncogenes in human disease. Zebrafish ERMS contain small, focal
regions of low-copy amplification. These same regions were commonly amplified in human disease. For example, 16 of 19
chromosomal gains identified in zebrafish ERMS also exhibited focal, low-copy gains in human disease. Genes found in
amplified genomic regions were assessed for functional roles in promoting continued tumor growth in human and
zebrafish ERMS – identifying critical genes associated with tumor maintenance. Knockdown studies identified important
roles for Cyclin D2 (CCND2), Homeobox Protein C6 (HOXC6) and PlexinA1 (PLXNA1) in human ERMS cell proliferation.
PLXNA1 knockdown also enhanced differentiation, reduced migration, and altered anchorage-independent growth. By
contrast, chemical inhibition of vascular endothelial growth factor (VEGF) signaling reduced angiogenesis and tumor size
in ERMS-bearing zebrafish. Importantly, VEGFA expression correlated with poor clinical outcome in patients with ERMS,
implicating inhibitors of the VEGF pathway as a promising therapy for improving patient survival. Our results demonstrate
the utility of array CGH and cross-species comparisons to identify candidate oncogenes essential for the pathogenesis of
human cancer.
Description
Copyright: 2013 Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits
unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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Keywords
Zebra danio, Comparative genomic hybridization, Rhabdomyosaroma, Cytogenetic studies
Citation
Chen EY, Dobrinski KP, Brown KH, Clagg R, Edelman E, et al. (2013) Cross-Species Array Comparative Genomic Hybridization Identifies Novel Oncogenic Events in Zebrafish and Human Embryonal Rhabdomyosarcoma. PLoS Genet 9(8): e1003727. doi:10.1371/journal.pgen.1003727