Glutamine deprivation alters the origin and function of cancer cell exosomes

Exosomes are secreted extracellular vesicles carrying diverse molecular cargos, which can modulate recipient cell behaviour. They are thought to derive from intraluminal vesicles formed in late endosomal multivesicular bodies (MVBs). An alternate exosome formation mechanism, which is conserved from...

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Published in:	The EMBO journal Vol. 39; no. 16; pp. e103009 - n/a
Main Authors:	Fan, Shih‐Jung, Kroeger, Benjamin, Marie, Pauline P, Bridges, Esther M, Mason, John D, McCormick, Kristie, Zois, Christos E, Sheldon, Helen, Khalid Alham, Nasullah, Johnson, Errin, Ellis, Matthew, Stefana, Maria Irina, Mendes, Cláudia C, Wainwright, Stephen Mark, Cunningham, Christopher, Hamdy, Freddie C, Morris, John F, Harris, Adrian L, Wilson, Clive, Goberdhan, Deborah CI
Format:	Journal Article
Language:	English
Published:	London Nature Publishing Group UK 17.08.2020 Springer Nature B.V John Wiley and Sons Inc
Subjects:	AKT protein Amphiregulin Animal models Animals Antibodies Blood vessels Cancer Cell Proliferation Depletion Deprivation Drosophila melanogaster Drosophila Proteins - genetics Drosophila Proteins - metabolism EMBO03 EMBO20 EMBO21 Endosomes Epidermal growth factor receptors exosome Exosomes Exosomes - genetics Exosomes - metabolism Exosomes - pathology extracellular vesicle Extracellular vesicles Glutamine Glutamine - deficiency Guanosine triphosphatases Heterogeneity Ligands MAP kinase MAP Kinase Signaling System mechanistic Target of Rapamycin Mechanistic Target of Rapamycin Complex 1 - genetics Mechanistic Target of Rapamycin Complex 1 - metabolism Metabolism multivesicular body Neoplasms - genetics Neoplasms - metabolism Neoplasms - pathology Protein turnover rab GTP-Binding Proteins - genetics rab GTP-Binding Proteins - metabolism Rab11(a) Rapamycin Signaling Substrates TOR protein Tumors Vesicles Xenografts Xenotransplantation mechanistic Target of Rapamycin Rab11(a) exosome extracellular vesicle multivesicular body
ISSN:	0261-4189, 1460-2075, 1460-2075
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Summary:	Exosomes are secreted extracellular vesicles carrying diverse molecular cargos, which can modulate recipient cell behaviour. They are thought to derive from intraluminal vesicles formed in late endosomal multivesicular bodies (MVBs). An alternate exosome formation mechanism, which is conserved from fly to human, is described here, with exosomes carrying unique cargos, including the GTPase Rab11, generated in Rab11‐positive recycling endosomal MVBs. Release of Rab11‐positive exosomes from cancer cells is increased relative to late endosomal exosomes by reducing growth regulatory Akt/mechanistic Target of Rapamycin Complex 1 (mTORC1) signalling or depleting the key metabolic substrate glutamine, which diverts membrane flux through recycling endosomes. Vesicles produced under these conditions promote tumour cell proliferation and turnover and modulate blood vessel networks in xenograft mouse models in vivo . Their growth‐promoting activity, which is also observed in vitro , is Rab11a‐dependent, involves ERK‐MAPK‐signalling and is inhibited by antibodies against amphiregulin, an EGFR ligand concentrated on these vesicles. Therefore, glutamine depletion or mTORC1 inhibition stimulates release from Rab11a compartments of exosomes with pro‐tumorigenic functions, which we propose promote stress‐induced tumour adaptation. Synopsis Heterogeneity of extracellular vesicles and their behaviour under metabolic stress conditions remain poorly understood. Here, reduction in glutamine levels or Akt/mTORC1 signalling are shown to induce cancer cell exosomes with altered cargos and increased pro‐tumorigenic functions, which are secreted from previously undescribed Rab11a‐dependent endosomes. Rab11a‐positive endosomal multivesicular bodies give rise to exosomes with distinct functions. Depletion of glutamine or Akt/mTORC1 induces Rab11a‐exosome release from cancer cells. Rab11a‐positive stress‐induced vesicles promote cancer cell and vessel growth in vitro and in vivo . An antibody against EGFR ligand, AREG, blocks Rab11a‐exosome‐induced tumour growth. Graphical Abstract Release of Rab11a‐positive exosomes with distinct cargos and increased pro‐tumorigenic functions is dependent on glutamine levels and Akt/mTORC1 signalling.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 ObjectType-Undefined-3 See also: G van Niel & C Théry (August 2020) These authors contributed equally to this work
ISSN:	0261-4189 1460-2075 1460-2075
DOI:	10.15252/embj.2019103009