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 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 5

GDF6-induced BMP signaling blocks melanoma cell differentiation.

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GDF6-induced BMP signaling blocks melanoma cell differentiation. (A) p-...
(A) p-SMAD1/5/8 binding to the MITF locus in A375 melanoma cells expressing an shRNA targeting EGFP or the GDF6-targeted shRNA GDF6.1. Traces of 2 independent biological replicates are shown. (B) qRT-PCR analysis showing expression of MITF in A375 empty or A375-SMAD1DVD cells expressing an shRNA targeting EGFP or the GDF6-targeted shRNA GDF6.1. (C) qRT-PCR analysis of TRP1 under the same conditions. Left brackets: MITF or TRP1 expression was upregulated upon GDF6 knockdown. Right brackets, MITF or TRP1 expression was less upregulated in SMAD1DVD-expressing cells upon GDF6 knockdown. Error bars represent the mean ± SEM. n = 3. (D) qRT-PCR analysis showing expression of mitfa and trp1b in control and gdf6a(lf) zebrafish melanomas. Error bars represent the mean ± SEM. n = 3. (E) H&E staining of transverse sections from Tg(mitfa:BRAFV600E);p53(lf) and Tg(mitfa:BRAFV600E);p53(lf);gdf6a(lf) zebrafish melanomas invading the dorsal musculature. Scale bars: 100 μm (left) and 25 μm (right). *P < 0.05 and ***P < 0.001, by 1-way ANOVA with Bonferroni’s test (B and C) or 2-tailed Student’s t test (D).