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PINK1 drives production of mtDNA-containing extracellular vesicles to promote invasiveness. | LitMetric

AI Article Synopsis

  • Scientists found that a special transporter called xCT helps cancer cells make a substance called glutathione, which helps them survive tough conditions.
  • When xCT is increased, it raises levels of a chemical called glutamate, which makes cancer cells act more aggressive and invade other areas.
  • Cancer cells release tiny packages called extracellular vesicles (EVs) that contain important materials like mitochondrial DNA, which can help other tumor cells become more invasive too.

Article Abstract

The cystine-glutamate antiporter, xCT, supports a glutathione synthesis program enabling cancer cells to cope with metabolically stressful microenvironments. Up-regulated xCT, in combination with glutaminolysis, leads to increased extracellular glutamate, which promotes invasive behavior by activating metabotropic glutamate receptor 3 (mGluR3). 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 "recipient" tumor cells. These EVs contain mitochondrial DNA (mtDNA), which is packaged via a PINK1-dependent mechanism. 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. 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8641410PMC
http://dx.doi.org/10.1083/jcb.202006049DOI Listing

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