Journal
NATURE
Volume 554, Issue 7692, Pages 378-+Publisher
NATURE PORTFOLIO
DOI: 10.1038/nature25465
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Funding
- Cancer Center Support Grant [5P30CA045508]
- The Hope Funds for Cancer Research
- Human Frontier Science Program
- Susan G. Komen Foundation [SAC110006]
- NCI Breast SPORE program [P50-CA58223-09A1]
- Breast Cancer Research Foundation
- Triple Negative Breast Cancer Foundation
- National Institutes of Health (NIH) [NCI R00 CA194077]
- Institute of Cancer Research, London
- Cancer Research UK [C59824/A25044]
- NIH [5 P01 CA013106-44]
- Department of Defense Breast Cancer Research Program [W81XWH-12-1-0300]
- Cancer Research UK [22310, 21143] Funding Source: researchfish
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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 sites(1). 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.
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