Glutamine deprivation alters the origin and function of cancer cell exosomes

Shih Jung Fan, Benjamin Kroeger, Pauline P. Marie, Esther M. Bridges, John D. Mason, Kristie McCormick, Christos E. Zois, Helen Sheldon, Nasullah Khalid Alham, Errin Johnson, Matthew Ellis, Maria Irina Stefana, Cláudia C. Mendes, Stephen Mark Wainwright, Christopher Cunningham, Freddie C. Hamdy, John F. Morris, Adrian L. Harris, Clive Wilson, Deborah C.I. Goberdhan

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1 Citation (Scopus)

Abstract

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.

Original languageEnglish
Article numbere103009
Number of pages27
JournalThe EMBO Journal
Volume39
Issue number16
DOIs
Publication statusPublished - 17 Aug 2020
Externally publishedYes

Keywords

  • exosome
  • extracellular vesicle
  • mechanistic Target of Rapamycin
  • multivesicular body
  • Rab11(a)

Cite this

Fan, S. J., Kroeger, B., Marie, P. P., Bridges, E. M., Mason, J. D., McCormick, K., Zois, C. E., Sheldon, H., Khalid Alham, N., Johnson, E., Ellis, M., Stefana, M. I., Mendes, C. C., Wainwright, S. M., Cunningham, C., Hamdy, F. C., Morris, J. F., Harris, A. L., Wilson, C., & Goberdhan, D. C. I. (2020). Glutamine deprivation alters the origin and function of cancer cell exosomes. The EMBO Journal, 39(16), [e103009]. https://doi.org/10.15252/embj.2019103009