Glutaminolysis drives membrane trafficking to promote invasiveness of breast cancer cells

Dornier, E. et al. (2017) Glutaminolysis drives membrane trafficking to promote invasiveness of breast cancer cells. Nature Communications, 8(1), 2255. (doi:10.1038/s41467-017-02101-2) (PMID:29269878) (PMCID:PMC5740148)

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Abstract

The role of glutaminolysis in providing metabolites to support tumour growth is well-established, but the involvement of glutamine metabolism in invasive processes is yet to be elucidated. Here we show that normal mammary epithelial cells consume glutamine, but do not secrete glutamate. Indeed, low levels of extracellular glutamate are necessary to maintain epithelial homoeostasis, and provision of glutamate drives disruption of epithelial morphology and promotes key characteristics of the invasive phenotype such as lumen-filling and basement membrane disruption. By contrast, primary cultures of invasive breast cancer cells convert glutamine to glutamate which is released from the cell through the system Xc- antiporter to activate a metabotropic glutamate receptor. This contributes to the intrinsic aggressiveness of these cells by upregulating Rab27-dependent recycling of the transmembrane matrix metalloprotease, MT1-MMP to promote invasive behaviour leading to basement membrane disruption. These data indicate that acquisition of the ability to release glutamate is a key watershed in disease aggressiveness.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Pallares Masmitja, Ms Maria and Blyth, Dr Karen and Sumpton, Mr David and MacPherson, Dr Iain and Mackay, Dr Gillian and Norman, Professor James and Novo, David and Mitchell, Mrs Louise and Rabas, Nicolas and Rainero, Ms Elena and Nixon, Mr Colin and Dornier, Mr Emmanuel Greg
Authors: Dornier, E., Rabas, N., Mitchell, L., Novo, D., Dhayade, S., Marco, S., Mackay, G., Sumpton, D., Pallares, M., Nixon, C., Blyth, K., MacPherson, I. R., Rainero, E., and Norman, J. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Nature Communications
ISSN:2041-1723
Copyright Holders:Copyright © 2017 The Authors
First Published:First published in Nature Communications 8(1):2255
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
647981CR-UK Centre renewalKaren VousdenCancer Research UK (CRUK)18076RI CANCER SCIENCES