Editors' ChoiceCell Biology

Flipping an exosome switch

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Science Signaling  01 Sep 2020:
Vol. 13, Issue 647, eabe5296
DOI: 10.1126/scisignal.abe5296

Nutrient stress changes the biogenesis and biological activity of exosomes in cancer cells.

Exosomes mediate the transfer of proteins, lipids, and nucleic acids between cells. They are generally thought to be produced by the inward budding of the late endosomal membrane, resulting in the formation of multivesicular bodies (MVBs) that fuse with the plasma membrane, releasing the exosomes extracellularly. Fan et al. found that fly and human cells contained MVBs derived from both Rab7-positive late endosomes and Rab11a-positive recycling endosomes. Exosomes from human colorectal cancer HCT116 cells and other cancer cell lines grown in low-glutamine conditions contained less late endosomal markers and much more Rab11a than did exosomes from cells grown under glutamine-replete conditions. Other exosomal cargo proteins were also differentially represented in the two populations of exosomes, including an increase in the epidermal growth factor receptor (EGFR) ligand amphiregulin in the exosomes from glutamine-depleted cells. Glutamine depletion inhibits mechanistic target of rapamycin complex 1 (mTORC1) signaling, and reducing mTORC1 signaling by other means also caused a similar change in the exosome population. Exosomes secreted under glutamine-depleted conditions stimulated the proliferation of naïve HCT116 cells and human umbilical vein endothelial cells (HUVECs) more than the control exosomes from cells grown under glutamine-replete conditions or exosomes from Rab11a-knockdown cells grown under glutamine-depleted conditions. Treating exosomes from glutamine-depleted cells with an amphiregulin-blocking antibody prevented them from stimulating HCT116 cell proliferation. Injecting exosomes from glutamine-depleted HCT116 cultures into HCT116 xenografts in mice stimulated more blood vessel growth compared with that induced by exosomes from glutamine-replete cultures. These findings show that nutrient stress can stimulate a switch in both the biogenesis pathway and content of exosomes, suggesting a possible explanation for the qualitative differences between exosomes produced in normal tissues and those produced in tumors.

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