Genomic analysis of metastasis reveals an essential role for RhoC

The most damaging change during cancer progression is the switch from a loc ally growing tumour to a metastatic killer. This switch is believed to invo lve numerous alterations that allow tumour cells to complete the complex se ries of events needed for metastasis(1). Relatively few genes have been imp licated in these events(2-5.) Here we use an in vivo selection scheme to se lect highly metastatic melanoma cells. By analysing these cells on DNA arra ys, we define a pattern of gene expression that correlates with progression to a metastatic phenotype. In particular, we show enhanced expression of s everal genes involved in extracellular matrix assembly and of a second set of genes that regulate, either directly or indirectly, the actin-based cyto skeleton. One of these, the small GTPase RhoC, enhances metastasis when ove rexpressed, whereas a dominant-negative Rho inhibits metastasis. Analysis o f the phenotype of cells expressing dominant-negative Rho or RhoC indicates that RhoC is important in tumour cell invasion. The genomic approach allow s us to identify families of genes involved in a process, not just single g enes, and can indicate which molecular and cellular events might be importa nt in complex biological processes such as metastasis.