Nature Genetics
37, 1047 - 1054 (2005)
Published online: 4 September 2005; | doi:10.1038/ng1634
The melanocyte differentiation program predisposes to metastasis after neoplastic transformationPiyush B Gupta1, 2, Charlotte Kuperwasser3, Jean-Philippe Brunet4, Sridhar Ramaswamy5, Wen-Lin Kuo6, Joe W Gray6, Stephen P Naber7
& Robert A Weinberg1, 21
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts
02142, USA. 2
Massachusetts Institute of Technology, Cambridge, Massachusetts
02142, USA. 3
Departments of Anatomy & Cellular Biology and Radiation Oncology, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts
02111, USA. 4
Broad Institute of MIT & Harvard, 320 Charles Street, Cambridge, Massachusetts
02141, USA. 5
Center for Cancer Research, Massachusetts General Hospital & Harvard Medical School, Building 149, 7th Floor, 13th Street, Charlestown, Massachusetts
02129, USA. 6
Department of Laboratory Medicine and UCSF Comprehensive Cancer Center, University of California San Francisco, San Francisco, California
94143, USA. 7
Department of Pathology, New England Medical Center, Tufts University School of Medicine, Boston, Massachusetts
02111, USA.
Correspondence should be addressed to Robert A Weinberg weinberg@wi.mit.edu The aggressive clinical behavior of melanoma suggests that the developmental origins of melanocytes in the neural crest might be relevant to their metastatic propensity. Here we show that primary human melanocytes, transformed using a specific set of introduced genes, form melanomas that frequently metastasize to multiple secondary sites, whereas human fibroblasts and epithelial cells transformed using an identical set of genes generate primary tumors that rarely do so. Notably, these melanomas have a metastasis spectrum similar to that observed in humans with melanoma. These observations indicate that part of the metastatic proclivity of melanoma is attributable to lineage-specific factors expressed in melanocytes and not in other cell types analyzed. Analysis of microarray data from human nevi shows that the expression pattern of Slug, a master regulator of neural crest cell specification and migration, correlates with those of other genes that are important for neural crest cell migrations during development. Moreover, Slug is required for the metastasis of the transformed melanoma cells. These findings indicate that melanocyte-specific factors present before neoplastic transformation can have a pivotal role in governing melanoma progression.
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