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

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

Research output: Contribution to journalArticlepeer-review

39 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)294-308
Number of pages15
JournalJournal of Clinical Investigation
Volume128
Issue number1
DOIs
StatePublished - Jan 2 2018

Bibliographical note

Funding Information:
We thank Eric Baehrecke, Nathan Lawson, Stephen Jones, and Leonard Zon for helpful discussions; Sarah Hainer and Thomas Fazzio for guidance with ChIP-seq experiments (all from University of Massachusetts Medical School, Worcester, MA, USA); Patrick White, Ed Jaskolski, and the staff at the UMMS Animal Medicine Department for fish care; Karen Sargent for mouse handling; the UMMS morphology core for sectioning and staining of slides; the UMMS Flow Cytometry Core for sorting experiments; the UMMS RNAi Core for providing shRNAs; Jia Xu, Jiang-Liang Li, and Feng Qi for bioinformatics support; Julie Zhu for assistance with statistical analysis; Melissa Kasheta for technical support; Revati Darp for assistance with xenografts; Fang Liu for assistance with tissue culture; Lin Lin for assistance with zebrafish melanocyte isolation; Paul Kaufman for LentiCMVHygro clones; Phil Zamore for use of the Covaris Ultrasonicator; and Takenobu Katagiri for the SMAD1DVD construct (all from University of Massachusetts Medical School, Worcester, MA, USA). We acknowledge the ENCODE Consortium and Thomas Gingeras’s laboratory for human melanocyte RNA-seq data generation. We thank Roger Davis (University of Massachusetts Medical School, Worcester, MA USA) for reviewing the manuscript. CBFG was supported by Karina G. Zecchin and the Brazilian Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) program. Research was supported by the Kimmel Scholar Award SKF-13-123; Department of Defense Peer Reviewed Cancer Research Program Career Development award W81XWH-13-0107; Worcester Foundation award P60016170000122; and NIH National Institute of Arthritis and Musculoskeletal and Skin Diseases grant R01 AR063850 (to CJC). The content is solely the responsibility of the authors and does not necessarily represent the official views of the Department of Defense or NIH.

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