UMMS Affiliation

Program in Molecular Medicine; Department of Molecular Cell and Cancer Biology; Department of Pathology

Publication Date

1-2-2018

Document Type

Article

Disciplines

Cancer Biology | Cell Biology | Neoplasms | Oncology

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.

Keywords

Cancer, Development, Oncology

Rights and Permissions

Copyright © 2018, American Society for Clinical Investigation. Open Access: The JCI is an open access journal. Publisher PDF posted as allowed by the publisher's author rights policy at https://www.jci.org/kiosks/terms.

DOI of Published Version

10.1172/JCI92513

Source

J Clin Invest. 2018 Jan 2;128(1):294-308. doi: 10.1172/JCI92513. Epub 2017 Dec 4. Link to article on publisher's site

Journal/Book/Conference Title

The Journal of clinical investigation

Related Resources

Link to Article in PubMed

PubMed ID

29202482

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