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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Vydáno v:The EMBO journal Ročník 39; číslo 16; s. e103009 - n/a
Hlavní autoři: 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
Médium: Journal Article
Jazyk:angličtina
Vydáno: London Nature Publishing Group UK 17.08.2020
Springer Nature B.V
John Wiley and Sons Inc
Témata:
ISSN:0261-4189, 1460-2075, 1460-2075
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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. 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.
AbstractList 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.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.
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.
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. Release of Rab11a‐positive exosomes with distinct cargos and increased pro‐tumorigenic functions is dependent on glutamine levels and Akt/mTORC1 signalling.
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.
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.
Author Mason, John D
McCormick, Kristie
Goberdhan, Deborah CI
Bridges, Esther M
Harris, Adrian L
Kroeger, Benjamin
Marie, Pauline P
Ellis, Matthew
Zois, Christos E
Khalid Alham, Nasullah
Morris, John F
Cunningham, Christopher
Mendes, Cláudia C
Sheldon, Helen
Hamdy, Freddie C
Johnson, Errin
Wilson, Clive
Fan, Shih‐Jung
Wainwright, Stephen Mark
Stefana, Maria Irina
AuthorAffiliation 1 Department of Physiology, Anatomy and Genetics University of Oxford Oxford UK
4 Nuffield Department of Surgical Sciences Oxford NIHR Biomedical Research Centre (BRC) John Radcliffe Hospital University of Oxford Oxford UK
6 Nuffield Department of Surgical Sciences John Radcliffe Hospital University of Oxford Oxford UK
2 Department of Oncology Weatherall Institute of Molecular Medicine University of Oxford Oxford UK
5 Sir William Dunn School of Pathology University of Oxford Oxford UK
3 Institute of Biomedical Engineering Department of Engineering Science University of Oxford Oxford UK
AuthorAffiliation_xml – name: 3 Institute of Biomedical Engineering Department of Engineering Science University of Oxford Oxford UK
– name: 4 Nuffield Department of Surgical Sciences Oxford NIHR Biomedical Research Centre (BRC) John Radcliffe Hospital University of Oxford Oxford UK
– name: 5 Sir William Dunn School of Pathology University of Oxford Oxford UK
– name: 1 Department of Physiology, Anatomy and Genetics University of Oxford Oxford UK
– name: 6 Nuffield Department of Surgical Sciences John Radcliffe Hospital University of Oxford Oxford UK
– name: 2 Department of Oncology Weatherall Institute of Molecular Medicine University of Oxford Oxford UK
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  surname: Fan
  fullname: Fan, Shih‐Jung
  organization: Department of Physiology, Anatomy and Genetics, University of Oxford
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  givenname: Benjamin
  orcidid: 0000-0003-1479-3841
  surname: Kroeger
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  organization: Department of Physiology, Anatomy and Genetics, University of Oxford
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  fullname: Marie, Pauline P
  organization: Department of Physiology, Anatomy and Genetics, University of Oxford
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  surname: Bridges
  fullname: Bridges, Esther M
  organization: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford
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  surname: Mason
  fullname: Mason, John D
  organization: Department of Physiology, Anatomy and Genetics, University of Oxford
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  surname: McCormick
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  organization: Department of Physiology, Anatomy and Genetics, University of Oxford
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  fullname: Zois, Christos E
  organization: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford
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  surname: Sheldon
  fullname: Sheldon, Helen
  organization: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford
– sequence: 9
  givenname: Nasullah
  surname: Khalid Alham
  fullname: Khalid Alham, Nasullah
  organization: Institute of Biomedical Engineering, Department of Engineering Science, University of Oxford, Nuffield Department of Surgical Sciences, Oxford NIHR Biomedical Research Centre (BRC), John Radcliffe Hospital, University of Oxford
– sequence: 10
  givenname: Errin
  surname: Johnson
  fullname: Johnson, Errin
  organization: Sir William Dunn School of Pathology, University of Oxford
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  givenname: Matthew
  surname: Ellis
  fullname: Ellis, Matthew
  organization: Department of Physiology, Anatomy and Genetics, University of Oxford
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  givenname: Maria Irina
  surname: Stefana
  fullname: Stefana, Maria Irina
  organization: Department of Physiology, Anatomy and Genetics, University of Oxford
– sequence: 13
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  surname: Mendes
  fullname: Mendes, Cláudia C
  organization: Department of Physiology, Anatomy and Genetics, University of Oxford
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  givenname: Stephen Mark
  surname: Wainwright
  fullname: Wainwright, Stephen Mark
  organization: Department of Physiology, Anatomy and Genetics, University of Oxford
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  surname: Cunningham
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  organization: Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford
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  surname: Hamdy
  fullname: Hamdy, Freddie C
  organization: Nuffield Department of Surgical Sciences, John Radcliffe Hospital, University of Oxford
– sequence: 17
  givenname: John F
  surname: Morris
  fullname: Morris, John F
  organization: Department of Physiology, Anatomy and Genetics, University of Oxford
– sequence: 18
  givenname: Adrian L
  surname: Harris
  fullname: Harris, Adrian L
  organization: Department of Oncology, Weatherall Institute of Molecular Medicine, University of Oxford
– sequence: 19
  givenname: Clive
  orcidid: 0000-0003-0040-0728
  surname: Wilson
  fullname: Wilson, Clive
  organization: Department of Physiology, Anatomy and Genetics, University of Oxford
– sequence: 20
  givenname: Deborah CI
  orcidid: 0000-0003-0645-6714
  surname: Goberdhan
  fullname: Goberdhan, Deborah CI
  email: deborah.goberdhan@dpag.ox.ac.uk
  organization: Department of Physiology, Anatomy and Genetics, University of Oxford
BackLink https://www.ncbi.nlm.nih.gov/pubmed/32720716$$D View this record in MEDLINE/PubMed
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DOI 10.15252/embj.2019103009
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Issue 16
Keywords mechanistic Target of Rapamycin
Rab11(a)
exosome
extracellular vesicle
multivesicular body
Language English
License Attribution
2020 The Authors. Published under the terms of the CC BY 4.0 license.
This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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See also: G van Niel & C Théry (August 2020)
These authors contributed equally to this work
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32809264 - EMBO J. 2020 Aug 17;39(16):e105119. doi: 10.15252/embj.2020105119.
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Snippet Exosomes are secreted extracellular vesicles carrying diverse molecular cargos, which can modulate recipient cell behaviour. They are thought to derive from...
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StartPage e103009
SubjectTerms 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
Title Glutamine deprivation alters the origin and function of cancer cell exosomes
URI https://link.springer.com/article/10.15252/embj.2019103009
https://onlinelibrary.wiley.com/doi/abs/10.15252%2Fembj.2019103009
https://www.ncbi.nlm.nih.gov/pubmed/32720716
https://www.proquest.com/docview/2434379608
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https://pubmed.ncbi.nlm.nih.gov/PMC7429491
Volume 39
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