Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma
Authors
Venkatesan, ArvindVyas, Rajesh
Gramann, Alec
Dresser, Karen A.
Gujja, Sharvari
Bhatnagar, Sanchita
Chhangawala, Sagar
Gomes, Camilla Borges Ferreira
Xi, Hualin Simon
Lian, Christine G.
Houvras, Yariv
Edwards, Yvonne J. K.
Deng, April C.
Green, Michael R.
Ceol, Craig J
UMass Chan Affiliations
Department of PathologyDepartment of Molecular Cell and Cancer Biology
Program in Molecular Medicine
Document Type
Journal ArticlePublication Date
2018-01-02
Metadata
Show full item recordAbstract
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.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
DOI
10.1172/JCI92513Permanent Link to this Item
http://hdl.handle.net/20.500.14038/40533PubMed ID
29202482Related Resources
Rights
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.ae974a485f413a2113503eed53cd6c53
10.1172/JCI92513