Glutaminolysis drives membrane trafficking to promote invasiveness of breast cancer cells

Emmanuel Dornier, Nicolas Rabas, Louise Mitchell, David Novo, Sandeep Dhayade, Sergi Marco, Gillian Mackay, David Sumpton, Maria Pallares, Colin Nixon, Karen Blyth, Iain R. Macpherson, Elena Rainero () and Jim C. Norman ()
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Emmanuel Dornier: Garscube Estate
Nicolas Rabas: Garscube Estate
Louise Mitchell: Garscube Estate
David Novo: Garscube Estate
Sandeep Dhayade: Garscube Estate
Sergi Marco: Garscube Estate
Gillian Mackay: Garscube Estate
David Sumpton: Garscube Estate
Maria Pallares: Garscube Estate
Colin Nixon: Garscube Estate
Karen Blyth: Garscube Estate
Iain R. Macpherson: Garscube Estate
Elena Rainero: Garscube Estate
Jim C. Norman: Garscube Estate

Nature Communications, 2017, vol. 8, issue 1, 1-14

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-02101-2

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