Ligand-activated BMP signaling inhibits cell differentiation and death to promote melanoma
| Autor: | Camilla Borges Ferreira Gomes, April Deng, Rajesh Vyas, Alec K. Gramann, Yvonne J. K. Edwards, Arvind M. Venkatesan, Sanchita Bhatnagar, Sharvari Gujja, Karen Dresser, Sagar Chhangawala, Hualin Simon Xi, Michael R. Green, Craig J. Ceol, Yariv Houvras, Christine G. Lian |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cellular differentiation Nude Immunology Mice Nude Development Growth Differentiation Factor 6 Oncogenomics Biology Ligands Medical and Health Sciences Cell Line Mice 03 medical and health sciences Melanocyte differentiation Cell Line Tumor Genetics medicine Animals Humans Melanoma Inbred BALB C Cancer Mice Inbred BALB C Microphthalmia-Associated Transcription Factor Tumor Oncogene Cell Differentiation General Medicine Gene signature Microphthalmia-associated transcription factor medicine.disease Neoplasm Proteins HEK293 Cells 030104 developmental biology Oncology Tumor progression Bone Morphogenetic Proteins Cancer research Female Research Article Signal Transduction |
| Zdroj: | The Journal of clinical investigation, vol 128, iss 1 |
| ISSN: | 1558-8238 0021-9738 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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