Metabolic rewiring drives invasion and metastasis in mammary carcinoma

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• Jim Norman, Cancer Research UK Beatson Institute
• Friday 29 October 2021, 13:00-14:00
• CRUK CI Lecture Theatre.

If you have a question about this talk, please contact Kate Davenport.

**Please register in advance for this seminar. Thank you. https://www.eventbrite.co.uk/e/190513820967**

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.

This talk is part of the Cancer Research UK Cambridge Institute (CRUK CI) Seminars in Cancer series.

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