Recent research has revealed two genes that may engender a predisposition to increased risk of metastasis in individual patients or specific tumor types—potentially important developments in the fight against cancer.

Tumor metastasis has bleak implications for patient survival and is recognized as the primary cause of cancer mortality. Unfortunately, it has proven difficult to confidently identify genes or mutations involved in the progression to metastatic disease. However, two articles published recently in Nature Genetics may offer important progress in this continuing search.

In the first article, researchers led by Kent Hunter of the National Cancer Institute (Bethesda, MD) analyzed a chromosomal region previously linked to metastasis of mammary tumors in mice (published online 4 September; doi: 10.1038/ng1635). By comparing this region in different mouse strains with especially high or low metastatic efficiency, the researchers identified 23 candidate genes, which they first prioritized in terms of their probable role in tumor progression and then analyzed in terms of expression patterns and strain-specific sequence variations. This led the team to the gene encoding Sipa1, a signaling protein with a specific mutation in metastasis-prone mouse strains that prevents it from interacting with a key repressor.

Mice implanted with mammary tumor cells with reduced Sipa1 expression showed a significant decrease in metastatic progression; moreover, when cultured, these cells showed enhanced adhesion properties. On the other hand, mice implanted with cells overexpressing Sipa1 showed double the number of metastases seen in mice implanted with unmodified tumor cells. The authors suggest that Sipa1 could function importantly in regulating cell morphology and adhesion, and that patients harboring mutations in this gene could face a congenital disadvantage subsequent to the onset of cancer.

In the same issue, Massachusetts Institute of Technology (Cambridge, MA) investigator Robert Weinberg and his colleagues examine melanoma, a cancer type known for its potential to metastasize rapidly (doi: 10.1038/ng1634). During development, dermal melanocyte precursors migrate from the neural crest, and Weinberg's group speculated that these migratory properties could predispose melanocytes to form highly metastatic tumors. Mice subcutaneously injected with retrovirally transformed melanocytes developed tumors that readily metastasized to a wide variety of tissues; when examination of the resulting nodules revealed that metastasis did not seem to result from gross genomic alterations, Weinberg's team looked at the expression patterns of genes linked to neural crest cell migration. One such gene, encoding the transcription factor Slug, seems to regulate the expression of other migration-related genes; when mice were injected with melanocytes in which Slug levels were sharply reduced through RNA interference, there was a reduction by an entire order of magnitude in the extent of metastasis, suggesting that dysregulation of this developmental pathway may be a key step in melanoma metastasis.