1. Howard Hughes Medical Institute, Centre for Cancer Research, and
2. Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA
3. Whitehead Institute/MIT Centre for Genome Research, 9 Cambridge Centre, Cambridge , Massachusetts 02142, USA
4. Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA
5. Present address: Millennium Predictive Medicine, One Kendall Square, Cambridge, Massachusetts 02139, USA.

Correspondence to: Correspondence and requests for materials should be addressed to R.O.H. (e-mail: Email: rohynes@mit.edu).

Abstract

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 metastasis¹. Relatively few genes have been implicated in these events^{2, 3, 4, 5}. 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.