As metastasis of primary cancers is the main cause of mortality in individuals with cancer, the identification of proteins that are important for this process is essential. Now, two groups report in Nature Medicine that ezrin is upregulated in metastatic cancers, and is key to the metastatic process.

Glenn Merlino and colleagues used a rhabdomyosarcoma mouse model to establish cell lines that were either highly or poorly metastatic when injected into mice. They then performed microarray expression profiling to identify genes that were differentially expressed. Two genes that were highly overexpressed — confirmed by western and northern blots — in the metastatic cell lines were those that encode ezrin and the homeoprotein transcription factor Six1.

But do they really contribute to metastasis? Overexpression of either gene in poorly metastatic cell lines increased their metastatic potential in mice by several fold. Similarly, disruption of the genes in highly metastatic cell lines diminished their metastatic ability. Interestingly, overexpression of Six1 seems to induce ezrin expression, forging a link between these two metastasis factors. Human rhabdomyosarcomas also have increased expression of these factors, which correlates with the disease stage.

Having previously identified ezrin in a genomic screen for metastasis-associated genes, Lee Helman and colleagues first confirmed its requirement by showing that its disruption — using an antisense approach or a phosphorylation mutant that keeps ezrin in the closed conformation — decreased metastasis in an experimental mouse osteosarcoma system.

They then used a single-cell fluorescent-imaging approach to follow the fate of cells that arrive in the lungs during metastasis. Cells in which ezrin was suppressed soon underwent apoptosis, so might ezrin inhibit anoikis? This would allow cells to survive in the lungs until they can attach to the tissue. The Akt and mitogen-activated protein kinase (MAPK) pathways have been implicated in anoikis inhibition, and ezrin was shown to decrease their activity. A constitutively active component of the MAPK pathway (Mek), but not activated Akt, was able to partially reconstitute metastasis in ezrin-suppressed cells.

Finally, the authors investigated the expression of ezrin in the highly metastatic spontaneous osteosarcomas that occur in pet dogs, as they are more relevant to humans. Ezrin was overexpressed in 83% of primary tumours, and its expression intensity correlated with the more aggressive tumours. Preliminary analysis indicates that the same is true in human paediatric osteosarcomas, which indicates that ezrin is an important regulator of metastasis that should be investigated further.