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Cited by 130Extracellular vesicles in diseaseCellular transport and secretionNanoparticle-Based Drug Delivery

Glutamine deprivation alters the origin and function of cancer cell exosomes

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Fan, Shih‐Jung, Kroeger, Benjamin, Marie, Pauline P, Bridges, Esther M, Mason, John D, McCormick, Kristie, Zois, Christos E, Sheldon, Helen +12 more·2020·The EMBO Journal
DOI 10.15252/embj.2019103009PMC PMC7429491

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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.

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Cited by

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Authors
Fan, S., 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.
Affiliations
  • University of Oxford (GB)
  • John Radcliffe Hospital (GB)
Corresponding author
Goberdhan, Deborah CI
ORCID
Venue
The EMBO Journal
Publisher
Springer Science and Business Media LLC
Published
2020-07-28
Volume
39
Issue
16
Pages
e103009-e103009
ISSN
  • 0261-4189 (ISSN-L)
  • 1460-2075
DOI
10.15252/embj.2019103009
PMC
PMC7429491
OpenAlex
W3033987764
Cited by
130
References
9
Citations by year
2026: 17 · 2025: 23 · 2024: 21 · 2023: 22 · 2022: 17 · 2021: 23 · 2020: 6 · 2019: 1
FWCI
5.49
Type
journal article
Language
en
Open access
Licence
Locations
  • The EMBO Journal (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Cancer Research UK (C19591/A19076, C38302/A12278, C602/A18974)
  • UK Research and Innovation | Biotechnology and Biological Sciences Research Council (BB/K017462/1, BB/L007096/1, BB/N016300/1, BB/R004862/1)
  • Breast Cancer Research Foundation (ANR 00162)
  • Wellcome Trust (091911, 107457, 102347/Z/13/Z)
  • National Institute for Health Research
  • Oxford University | John Fell Fund, University of Oxford (141/063)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Extracellular vesicles in disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular transport and secretion
  • Physical Sciences › Materials Science › Biomaterials › Nanoparticle-Based Drug Delivery
Keywords
exosomes, glutamine deprivation, Rab11a, recycling endosomes, multivesicular bodies, mTORC1 signaling, Akt signaling, extracellular vesicles, tumor cell proliferation, angiogenesis, ERK/MAPK signalling, amphiregulin, EGFR, cancer metabolism
MeSH terms
Mechanistic Target of Rapamycin Complex 1, rab11 GTP-Binding Proteins, Animals, Drosophila melanogaster, Glutamine, Neoplasms, rab GTP-Binding Proteins, MAP Kinase Signaling System, Drosophila Proteins, Cell Proliferation, Exosomes

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