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.
Highlights
Rhabdomyosaroma (RMS) is the most common soft tissue sarcoma of childhood [1] and falls into two major histopathologic subtypes in children - embryonal and alveolar
These latter two studies have demonstrated the utility of array CGH technology in detecting copy number aberrations and candidate driver genes in zebrafish tumor models, yet functional relevance of identified genes in human disease has not been reported nor have these genes been assessed for roles in regulating tumor maintenance
Array CGH was used in a zebrafish model of embryonal rhabdomyosarcoma - a pediatric muscle tumor
Summary
Rhabdomyosaroma (RMS) is the most common soft tissue sarcoma of childhood [1] and falls into two major histopathologic subtypes in children - embryonal and alveolar. Highresolution array CGH has been applied to zebrafish T-ALL and identified a subset of genes contained within CNAs that were amplified or deleted in human disease [20]. These latter two studies have demonstrated the utility of array CGH technology in detecting copy number aberrations and candidate driver genes in zebrafish tumor models, yet functional relevance of identified genes in human disease has not been reported nor have these genes been assessed for roles in regulating tumor maintenance – providing novel targets for therapy in established tumors
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