Glutamine deprivation alters the origin and function of cancer cell exosomes
| Autor: | Freddie C. Hamdy, Adrian L. Harris, Clive Wilson, Maria Irina Stefana, John F. Morris, Nasullah Khalid Alham, Helen Sheldon, Kristie McCormick, Deborah C.I. Goberdhan, Cláudia C. Mendes, Pauline P. Marie, Christos E. Zois, Matthew Ellis, Stephen Mark Wainwright, John D. Mason, Christopher M. Cunningham, Errin Johnson, Benjamin Kroeger, Esther Bridges, Shih-Jung Fan |
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| Rok vydání: | 2019 |
| Předmět: |
Endosome
MAP Kinase Signaling System Glutamine mTORC1 Biology Mechanistic Target of Rapamycin Complex 1 Exosomes Exosome Article multivesicular body General Biochemistry Genetics and Molecular Biology 03 medical and health sciences 0302 clinical medicine Neoplasms exosome Animals Drosophila Proteins News & Views Membrane & Intracellular Transport mechanistic Target of Rapamycin Molecular Biology Mechanistic target of rapamycin Cancer 030304 developmental biology Cell Proliferation 0303 health sciences General Immunology and Microbiology General Neuroscience Vesicle Articles Extracellular vesicle Microvesicles Cell biology Metabolism Drosophila melanogaster Rab11(a) rab GTP-Binding Proteins biology.protein extracellular vesicle 030217 neurology & neurosurgery |
| Zdroj: | EMBO J The EMBO Journal |
| ISSN: | 1460-2075 |
| Popis: | 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. Release of Rab11a‐positive exosomes with distinct cargos and increased pro‐tumorigenic functions is dependent on glutamine levels and Akt/mTORC1 signalling. |
| Databáze: | OpenAIRE |
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