Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma
Arvind M. Venkatesan, … , Michael Green, Craig J. Ceol
Arvind M. Venkatesan, … , Michael Green, Craig J. Ceol
Published January 2, 2018; First published December 4, 2017
Citation Information: J Clin Invest. 2018;128(1):294-308. https://doi.org/10.1172/JCI92513.
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Research Article Development Oncology

Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma

Abstract

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.

Authors

Arvind M. Venkatesan, Rajesh Vyas, Alec K. Gramann, Karen Dresser, Sharvari Gujja, Sanchita Bhatnagar, Sagar Chhangawala, Camilla Borges Ferreira Gomes, Hualin Simon Xi, Christine G. Lian, Yariv Houvras, Yvonne J. K. Edwards, April Deng, Michael Green, Craig J. Ceol

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Figure 1

GDF6 is recurrently amplified and specifically expressed in melanomas.

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GDF6 is recurrently amplified and specifically expressed in melanomas. ...
(A) Circos plot displaying gene copy number gains and losses of zebrafish melanomas across 25 chromosomes. JISTIC G-scores are displayed as pale red shading (amplifications [minimum = 0; maximum = 1,550]) and blue shading (deletions [minimum = 0; maximum = 2,150]). –log10-transformed JISTIC Q-values with a cutoff of 0.6 (corresponding to an untransformed Q-value of 0.25) are shown as bold red lines (amplifications [minimum = 0; maximum = 11]) and bold blue (deletions [minimum = 0; maximum = 11]). Dotted circles represent the –log10-transformed Q-value of 0 (center) and 11 (outer: amplification; inner: deletion). (B) Venn diagram of orthologous genes significantly amplified in human and zebrafish melanomas from a total of 10,380 human-zebrafish gene pairs (hypergeometric test, P value: 2.0 × 10–15). (C) Genes significantly upregulated in zebrafish melanomas as compared with melanocytes (microarray data set) are plotted in order of their fold change. Only genes with a fold change of greater than 2 and an adjusted P value of less than 0.05 are plotted. Recurrently amplified genes with amplified human orthologs are indicated in red. gdf6b (large red dot) and gdf6a (large black dot) are indicated. Dashed horizontal line represents a fold change of 2. (D) Immunostaining of Tg(mitfa:BRAFV600E);p53(lf) zebrafish scales bearing melanoma cells or normal melanocytes. DAPI (blue), Gdf6b (green), Mitfa (red), and a merged image of all channels are shown. Mitfa antibody specificity is shown in Supplemental Figure 2B. Scale bars: 10 μm.