Asparagine bioavailability governs metastasis in a model of breast cancer

Knott, S. R. V., Wagenblast, E., Khan, S., Kim, S. Y., Soto, M., Wagner, M., Turgeon, M. O., Fish, L., Erard, N., Gable, A. L., Maceli, A. R., Dickopf, S., Papachristou, E. K., D'Santos, C. S., Carey, L. A., Wilkinson, J. E., Harrell, J. C., Perou, C. M., Goodarzi, H., Poulogiannis, G., Hannon, G. J. (February 2018) Asparagine bioavailability governs metastasis in a model of breast cancer. Nature, 554 (7692). pp. 378-381. ISSN 0028-0836

URL: https://www.ncbi.nlm.nih.gov/pubmed/29414946
DOI: 10.1038/nature25465

Abstract

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. 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.

Item Type: Paper
Subjects: diseases & disorders > cancer > cancer types > breast cancer
diseases & disorders > cancer > metastasis
CSHL Authors:
Communities: CSHL labs > Hannon lab
Depositing User: Matt Covey
Date: 15 February 2018
Date Deposited: 07 Mar 2018 15:29
Last Modified: 14 Jun 2018 15:53
PMCID: PMC5898613
Related URLs:
URI: http://repository.cshl.edu/id/eprint/36202

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