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Nature. 2018 Feb 15;554(7692):378-381. doi: 10.1038/nature25465. Epub 2018 Feb 7.

Asparagine bioavailability governs metastasis in a model of breast cancer.

Author information

1
Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
2
Watson School of Biological Sciences, Howard Hughes Medical Institute, Cold Spring Harbor Laboratory, 1 Bungtown Road, Cold Spring Harbor, New York 11724, USA.
3
Center for Bioinformatics and Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048, USA.
4
Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
5
Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
6
New York Genome Center, 101 6th Avenue, New York, New York 10013, USA.
7
Division of Cancer Biology, The Institute of Cancer Research, 237 Fulham Road, London SW3 6JB, UK.
8
Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California 94158, USA.
9
Department of Urology, University of California, San Francisco, San Francisco, California 94158, USA.
10
Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, California 94158, USA.
11
Division of Hematology and Oncology, University of North Carolina at Chapel Hill, 170 Manning Drive, CB7305, Chapel Hill, North Carolina 27599, USA.
12
Department of Pathology, University of Michigan School of Medicine, Ann Arbor, Michigan 48109, USA.
13
Department of Pathology, Virginia Commonwealth University, Richmond, Virginia 23284, USA.
14
Department of Genetics and Pathology, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
15
Division of Computational and Systems Medicine, Department of Surgery and Cancer, Imperial College London, London SW7 2AZ, UK.

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.

PMID:
29414946
PMCID:
PMC5898613
DOI:
10.1038/nature25465
[Indexed for MEDLINE]
Free PMC Article

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