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.
Highlights
The role of glutaminolysis in providing metabolites to support tumour growth is wellestablished, but the involvement of glutamine metabolism in invasive processes is yet to be elucidated
An accepted watershed in breast cancer aggressiveness is the progression from ductal carcinoma in situ (DCIS), characterised by intraductal proliferation of malignant epithelial cells with an intact basement membrane, to invasive ductal carcinoma (IDC) in which the basement membrane becomes breached allowing dissemination of malignant cells[4]
We have measured the circulating levels of a broad range of metabolites during tumour progression in mammary tumour virus (MMTV)-polyoma middle T (PyMT) mice, and found that glutamate is the only one whose serum levels positively correlate with primary mammary tumour burden
Summary
The role of glutaminolysis in providing metabolites to support tumour growth is wellestablished, but the involvement of glutamine metabolism in invasive processes is yet to be elucidated. Primary cultures of invasive breast cancer cells convert glutamine to glutamate which is released from the cell through the system Xcantiporter 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. In this study we have found that high levels of glutamine consumption, in combination with functional expression of the system Xc- antiporter, contributes to cancer aggressiveness by generating a source of extracellular glutamate This extracellular glutamate activates the GRM3 metabotropic glutamate receptor to drive receptor recycling leading to basement membrane disruption and invasion in breast cancer
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