Glutaminolysis drives membrane trafficking to promote invasiveness of breast cancer cells

• Published in: Nature communications 2017-12, Vol.8 (1), p.2255-2255, Article 2255
• Main Authors: Dornier, Emmanuel, Rabas, Nicolas, Mitchell, Louise, Novo, David, Dhayade, Sandeep, Marco, Sergi, Mackay, Gillian, Sumpton, David, Pallares, Maria, Nixon, Colin, Blyth, Karen, Macpherson, Iain R., Rainero, Elena, Norman, Jim C.
• Format: Article
• Language: English
• Subjects: 631/67/2327; 631/80/313; 631/80/84/2336; Amino Acid Transport System y+ - metabolism; Animals; Breast cancer; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cancer; Cell Line, Tumor; Disruption; Epithelial cells; Extracellular Space - metabolism; Female; Glutamic Acid - metabolism; Glutamic acid receptors (metabotropic); Glutamine; Glutamine - metabolism; Homeostasis; Humanities and Social Sciences; Humans; Invasiveness; Mammary gland; Mammary Glands, Human - metabolism; Mammary Neoplasms, Animal - metabolism; Mammary Neoplasms, Animal - pathology; Matrix metalloproteinase; Matrix Metalloproteinase 14 - metabolism; Membrane trafficking; Metabolism; Metabolites; Metalloproteinase; Mice; multidisciplinary; Neoplasm Invasiveness; Physical characteristics; rab27 GTP-Binding Proteins - metabolism; Receptors, Metabotropic Glutamate - metabolism; Science; Science (multidisciplinary); Tumors; Up-Regulation; Watersheds
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-017-02101-2

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. Glutamine metabolism is well known to support tumour growth. Here the authors show that cancer cells also utilize glutamine to promote invasiveness by converting it to glutamate, which upon secretion activates metabotropic glutamate receptors to stimulate matrix metalloproteases recycling to the cell surface.