| Autor: |
Venkatesan AM; Program in Molecular Medicine.; Department of Molecular, Cell and Cancer Biology., Vyas R; Program in Molecular Medicine.; Department of Molecular, Cell and Cancer Biology., Gramann AK; Program in Molecular Medicine.; Department of Molecular, Cell and Cancer Biology., Dresser K; Department of Pathology, and., Gujja S; Program in Molecular Medicine., Bhatnagar S; Program in Molecular Medicine.; Department of Molecular, Cell and Cancer Biology.; Howard Hughes Medical Institute, University of Massachusetts Medical School (UMMS), Worcester, Massachusetts, USA., Chhangawala S; Departments of Surgery and Medicine, Weill Cornell Medical College, New York, New York, USA., Gomes CBF; Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Xi HS; Program in Molecular Medicine., Lian CG; Program in Dermatopathology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Houvras Y; Departments of Surgery and Medicine, Weill Cornell Medical College, New York, New York, USA., Edwards YJK; Program in Molecular Medicine., Deng A; Department of Pathology, and., Green M; Program in Molecular Medicine.; Department of Molecular, Cell and Cancer Biology.; Howard Hughes Medical Institute, University of Massachusetts Medical School (UMMS), Worcester, Massachusetts, USA., Ceol CJ; Program in Molecular Medicine.; Department of Molecular, Cell and Cancer Biology. |
| Abstrakt: |
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. |
