Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 128, Issue 1, Pages 294-308Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI92513
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Funding
- Brazilian Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior (CAPES)
- Kimmel Scholar Award [SKF-13-123]
- Department of Defense Peer Reviewed Cancer Research Program Career Development award [W81XWH-13-0107]
- Worcester Foundation [P60016170000122]
- NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases [R01 AR063850]
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Oncogenomic studies indicate that copy number variation (CNV) alters genes involved in tumor progression; however, identification of specific driver genes affected by CNV has been difficult, as these rearrangements are often contained in large chromosomal intervals among several bystander genes. Here, we addressed this problem and identified a CNV-targeted oncogene by performing comparative oncogenomics of human and zebrafish melanomas. We determined that the gene encoding growth differentiation factor 6 (GDF6), which is the ligand for the BMP family, is recurrently amplified and transcriptionally upregulated in melanoma. GDF6-induced BMP signaling maintained a trunk neural crest gene signature in melanomas. Additionally, GDF6 repressed the melanocyte differentiation gene MITF and the proapoptotic factor SOX9, thereby preventing differentiation, inhibiting cell death, and promoting tumor growth. GDF6 was specifically expressed in melanomas but not melanocytes. Moreover, GDF6 expression levels in melanomas were inversely correlated with patient survival. Our study has identified a fundamental role for GDF6 and BMP signaling in governing an embryonic cell gene signature to promote melanoma progression, thus providing potential opportunities for targeted therapy to treat GDF6-positive cancers.
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