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.

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Figure 1: Characterization of retrovirus-transduced primary human melanocytes.
Figure 2: Primary Mel-STR melanomas give rise to widespread metastases in vivo.
Figure 3: Primary Mel-STR melanomas rapidly seed distinct metastatic clones to secondary organs.
Figure 4: Suppression of Slug expression inhibits melanoma metastasis in vivo.

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Acknowledgements

We thank S. Dessain, H. Vaziri, P.A. Sharp, G. Gupta, S. Stewart, W. Hahn, A. Orimo, S. Godar, I. Ben-porath, J. Yang and T. Onder for discussions and suggestions during the course of this work; T. Golub for discussions regarding microarray experiments; T. Chavarria for assistance with animal husbandry; and D. LaCivita for primary melanocyte isolation. P.B.G. is supported by a US Army Pre-doctoral Breast Cancer Fellowship. This work was supported by a grant from the US National Institutes of Health and National Cancer Institute (R.A.W.). R.A.W. is an American Cancer Society Research Professor and a Daniel K. Ludwig Foundation Cancer Research Professor.

Author information

Correspondence to Robert A Weinberg.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Immunohistochemical characterization of Mel-STR lung metastases. (PDF 1078 kb)

Supplementary Fig. 2

Immunohistochemical characterization of subcutaneous Mel-STR tumors. (PDF 2363 kb)

Supplementary Fig. 3

Gross appearance of Mel-STR metastasis-laden organs. (PDF 4296 kb)

Supplementary Table 1

Genes significantly correlated in their expression patterns with Slug in human nevus samples (p<0.05). (PDF 106 kb)

Supplementary Note (PDF 75 kb)

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Gupta, P., Kuperwasser, C., Brunet, J. et al. The melanocyte differentiation program predisposes to metastasis after neoplastic transformation. Nat Genet 37, 1047–1054 (2005). https://doi.org/10.1038/ng1634

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