The melanocyte differentiation program predisposes to metastasis after neoplastic transformation.
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.
Gupta
Piyush B
PB
Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
Kuperwasser
Charlotte
C
Brunet
Jean-Philippe
JP
Ramaswamy
Sridhar
S
Kuo
Wen-Lin
WL
Gray
Joe W
JW
Naber
Stephen P
SP
Weinberg
Robert A
RA
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
D034741:RNA, Small Interfering; C000604407:SNAI1 protein, human; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors