Asparagine bioavailability governs metastasis in a model of breast cancer

In a mouse model of breast cancer, asparagine bioavailability strongly influences metastasis and this is correlated with the production of proteins that regulate the epithelial-to-mesenchymal transition, which provides at least one potential mechanism for how a single amino acid could regulate metastatic progression. Not all cells that derive from a primary tumour contribute to metastasis—the progression of cancer into other parts of the body. Gregory Hannon and colleagues find determinants of metastatic potential in a mouse model of breast cancer. They find that expression of the metabolic enzyme asparagine synthetase is associated with metastasis formation. Decreasing asparagine availability by treatment with ʟ-asparaginase or by dietary restriction reduced the development of metastasis. The authors show that asparagine availability promotes an epithelial-to-mesenchymal transition, a process that has been linked to metastasis. Using a functional model of breast cancer heterogeneity, we previously showed that clonal sub-populations proficient at generating circulating tumour cells were not all equally capable of forming metastases at secondary sites1. A combination of differential expression and focused in vitro and in vivo RNA interference screens revealed candidate drivers of metastasis that discriminated metastatic clones. Among these, asparagine synthetase expression in a patient’s primary tumour was most strongly correlated with later metastatic relapse. Here we show that asparagine bioavailability strongly influences metastatic potential. Limiting asparagine by knockdown of asparagine synthetase, treatment with l-asparaginase, or dietary asparagine restriction reduces metastasis without affecting growth of the primary tumour, whereas increased dietary asparagine or enforced asparagine synthetase expression promotes metastatic progression. Altering asparagine availability in vitro strongly influences invasive potential, which is correlated with an effect on proteins that promote the epithelial-to-mesenchymal transition. This provides at least one potential mechanism for how the bioavailability of a single amino acid could regulate metastatic progression.