Abstract

The CRUK -Beatson Institute has an ongoing programme to map cancer-associated metabolomic landscapes. This has indicated that alterations to the serum metabolome presage metastatic onset. In mammary cancers, elevated circulating glutamate is a prominent feature of the metastasis-associated metabolome, and this is owing to upregulated expression of the glutamate-cystine antiporter, xCT (SLC7A11) in metabolically-stressed cancer cells. Extracellular glutamate then activates a metabotropic glutamate receptor, mGluR3 to drive invasive behaviour by enlisting membrane trafficking events dependent on the Rab27 GTPase. Consistently, Rab27a knockout mice bearing autochthonous MMTV -PyMT mammary tumours display reduced metastasis to the lungs. Through exploring the cellular mechanisms responsible for this, we have found that Rab27a participates in a membrane trafficking process in which mitochondrial material (including mitochondrial DNA (mtDNA)) is packaged into exosomes. mtDNA-containing exosomes are then released from cancer cells to evoke invasive behaviour in neighbouring cells by activating a toll-like receptor, TLR9 . Thus, this work has led us to discover a pathway through which metabolic rewiring in cancers can drive invasion and metastasis by releasing mtDNA-containing exosomes to influence the behaviour of other cells in the tumour microenvironment and beyond.