ZFIN ID: ZDB-PUB-171205-14
Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma
Venkatesan, A.M., Vyas, R., Gramann, A.K., Dresser, K., Gujja, S., Bhatnagar, S., Chhangawala, S., Gomes, C.B.F., Xi, H.S., Lian, C.G., Houvras, Y., Edwards, Y.J.K., Deng, A., Green, M., Ceol, C.J.
Date: 2017
Source: The Journal of Clinical Investigation   128(1): 294-308 (Journal)
Registered Authors: Ceol, Craig, Houvras, Yariv
Keywords: Cancer, Development, Oncology
Microarrays: GEO:GSE83343, GEO:GSE83399, GEO:GSE83400
MeSH Terms:
  • Animals
  • Bone Morphogenetic Proteins/genetics
  • Bone Morphogenetic Proteins/metabolism*
  • Cell Differentiation*
  • Cell Line, Tumor
  • Female
  • Growth Differentiation Factor 6/genetics
  • Growth Differentiation Factor 6/metabolism*
  • HEK293 Cells
  • Humans
  • Ligands
  • Melanoma/genetics
  • Melanoma/metabolism*
  • Melanoma/pathology
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Microphthalmia-Associated Transcription Factor/genetics
  • Microphthalmia-Associated Transcription Factor/metabolism
  • Neoplasm Proteins/genetics
  • Neoplasm Proteins/metabolism*
  • Signal Transduction*
PubMed: 29202482 Full text @ Journal of Clin. Invest.
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.