Increased circulating glutamate has been reported in patients with cancer, and in the MMTV-PyMT autochthonous mouse model of mammary carcinoma using mice expressing the polyoma-middle-T (PyMT) oncogene under the control of the mammary epithelial mouse mammary tumor virus (MMTV) promoter, serum glutamate levels correlate closely with tumor burden ( Budczies et al., 2015 Dornier et al., 2017). Key to glutathione synthesis is the xCT cystine-glutamate antiporter (SLC7A11), which imports cystine at the expense of equimolar glutamate efflux ( Combs and DeNicola, 2019), and this leads to increased glutamate in the extracellular milieu. Tumor cells up-regulate glutaminolysis to support anaplerosis and growth while establishing cytoprotective programs, such as glutathione synthesis, to counteract metabolically stressful tumor microenvironments ( Zhu and Thompson, 2019). We propose that an EV-mediated mechanism, through which altered cellular metabolism in one cell influences endosomal trafficking in other cells, is key to generation and dissemination of pro-invasive microenvironments during mammary carcinoma progression.

We highlight mtDNA as a key EV cargo necessary and sufficient for intercellular transfer of invasive behavior by activating Toll-like receptor 9 in recipient cells, and this involves increased endosomal trafficking of pro-invasive receptors. These EVs contain mitochondrial DNA (mtDNA), which is packaged via a PINK1-dependent mechanism. Here we show that activation of mGluR3 in breast cancer cells activates Rab27-dependent release of extracellular vesicles (EVs), which can transfer invasive characteristics to вЂњrecipientвЂќ tumor cells. Up-regulated xCT, in combination with glutaminolysis, leads to increased extracellular glutamate, which promotes invasive behavior by activating metabotropic glutamate receptor 3 (mGluR3). The cystine-glutamate antiporter, xCT, supports a glutathione synthesis program enabling cancer cells to cope with metabolically stressful microenvironments.

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