title: The melanocyte differentiation program predisposes to metastasis after neoplastic transformation.
abstract: 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.
authors.affiliation: Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
authors.forename: Piyush B
authors.initials: PB
authors.lastname: Gupta
authors.forename: Charlotte
authors.initials: C
authors.lastname: Kuperwasser
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Brunet
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: Wen-Lin
authors.initials: WL
authors.lastname: Kuo
authors.forename: Joe W
authors.initials: JW
authors.lastname: Gray
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Naber
authors.forename: Robert A
authors.initials: RA
authors.lastname: Weinberg
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002454:Cell Differentiation; D002465:Cell Movement / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D008544:Melanocytes / Q000166:cytology / Q000378:metabolism* / Q000473:pathology; D008545:Melanoma / Q000235:genetics / Q000473:pathology*; D051379:Mice; D009362:Neoplasm Metastasis; D020411:Oligonucleotide Array Sequence Analysis; D034741:RNA, Small Interfering / Q000235:genetics; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors