Genomic analysis of metastasis reveals an essential role for RhoC.
The most damaging change during cancer progression is the switch from a locally growing tumour to a metastatic killer. This switch is believed to involve numerous alterations that allow tumour cells to complete the complex series of events needed for metastasis. Relatively few genes have been implicated in these events. Here we use an in vivo selection scheme to select highly metastatic melanoma cells. By analysing these cells on DNA arrays, we define a pattern of gene expression that correlates with progression to a metastatic phenotype. In particular, we show enhanced expression of several genes involved in extracellular matrix assembly and of a second set of genes that regulate, either directly or indirectly, the actin-based cytoskeleton. One of these, the small GTPase RhoC, enhances metastasis when overexpressed, whereas a dominant-negative Rho inhibits metastasis. Analysis of the phenotype of cells expressing dominant-negative Rho or RhoC indicates that RhoC is important in tumour cell invasion. The genomic approach allows us to identify families of genes involved in a process, not just single genes, and can indicate which molecular and cellular events might be important in complex biological processes such as metastasis.
Clark
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Howard Hughes Medical Institute, Centre for Cancer Research, Massachusetts Institute of Technology, Cambridge 02139, USA.
Golub
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Lander
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Hynes
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D000818:Animals; D005353:Fibronectins / Q000235:genetics / Q000502:physiology; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D018014:Gene Transfer Techniques; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D008545:Melanoma; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009154:Mutation; D009362:Neoplasm Metastasis / Q000235:genetics; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D013947:Thymosin / Q000235:genetics / Q000502:physiology; D014407:Tumor Cells, Cultured; D018631:ras Proteins; D020741:rho GTP-Binding Proteins / Q000235:genetics / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000502:physiology; D000075024:rhoC GTP-Binding Protein; D000099201:Thymosin beta(4)
D005353:Fibronectins; D013947:Thymosin; D018631:ras Proteins; D020741:rho GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D000075024:rhoC GTP-Binding Protein; D000099201:Thymosin beta(4); C066690:RHOC protein, human; C512911:Rhoc protein, mouse