Asparagine bioavailability governs metastasis in a model of breast cancer.
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Embargo End Date
ICR Authors
Authors
Knott, SRV
Wagenblast, E
Khan, S
Kim, SY
Soto, M
Wagner, M
Turgeon, M-O
Fish, L
Erard, N
Gable, AL
Maceli, AR
Dickopf, S
Papachristou, EK
D'Santos, CS
Carey, LA
Wilkinson, JE
Harrell, JC
Perou, CM
Goodarzi, H
Poulogiannis, G
Hannon, GJ
Wagenblast, E
Khan, S
Kim, SY
Soto, M
Wagner, M
Turgeon, M-O
Fish, L
Erard, N
Gable, AL
Maceli, AR
Dickopf, S
Papachristou, EK
D'Santos, CS
Carey, LA
Wilkinson, JE
Harrell, JC
Perou, CM
Goodarzi, H
Poulogiannis, G
Hannon, GJ
Document Type
Journal Article
Date
2018-02-15
Date Accepted
2017-12-15
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.
Citation
Nature, 2018, 554 (7692), pp. 378 - 381
Source Title
Publisher
NATURE PORTFOLIO
ISSN
0028-0836
eISSN
1476-4687
Collections
Research Team
Signalling & Cancer Metabolism