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 7

Clinical impact of GDF6 expression and BMP pathway inhibition.

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Clinical impact of GDF6 expression and BMP pathway inhibition. (A) H&amp...
(A) H&E, cytoplasmic GDF6, and nuclear p-SMAD1/5/8 immunostaining of adjacent normal skin and melanoma tissue from the same section. Melanocytes in normal skin sections are indicated by arrowheads. Images of individual cells are shown immediately to the right. Scale bars: 25 μm. Original magnification: ×63. Graphs indicate the percentage of patients’ samples with no or low expression or high expression of these proteins in normal melanocytes and melanomas. (B) Left, percentage of patients’ samples with no or low or high GDF6 expression in the melanoma tissue microarray. Graph of Kaplan-Meier analysis for the melanoma tissue microarray samples shows the overall survival of patients with no or low GDF6 expression (blue line) versus those with high GDF6 expression (red line). Statistical analysis was performed with a Mantel-Cox log-rank test. (C) GDF6 staining score in patients with primary melanomas with (n = 61) or without (n = 19) lymph node (LN) metastasis. **P < 0.01, by 2-tailed Welch’s test. (D) Mice bearing A375 xenografts were treated with vehicle, DMH1, dabrafenib plus trametinib, or a combination of all 3 drugs. Normalized tumor volumes following the beginning of drug treatments are shown. Error bars represent the mean ± SEM. n ≥ 8 animals. (E) Model for GDF6 activation and function in melanomas. **P < 0.01, by 1-way ANOVA with Bonferroni’s test (D); ##P < 0.001 by 1-way ANOVA (D).