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Ral GTPases promote metastasis by controlling biogenesis and organ colonization of exosomes

S Ghoroghi, B Mary, A Larnicol, A Klein, N Osmani, I Busnelli, F Delalande, N Paul, S Halary, F Gros, L Fouillen, AM Haeberle, C Royer, C Spiegelhalter, G André-Grégoire, K Murphy, P Timpson, R Carapito, M Blot-Chabaud, J Gavard, C Carapito, N Vitale, View ORCID ProfileO Lefebvre, View ORCID ProfileJG Goetz, View ORCID ProfileV Hyenne
doi: https://doi.org/10.1101/2020.07.10.196691
S Ghoroghi
1INSERM UMR S1109, Tumor Biomechanics, Strasbourg, France
2Université de Strasbourg, Strasbourg, France
3Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
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B Mary
1INSERM UMR S1109, Tumor Biomechanics, Strasbourg, France
2Université de Strasbourg, Strasbourg, France
3Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
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A Larnicol
1INSERM UMR S1109, Tumor Biomechanics, Strasbourg, France
2Université de Strasbourg, Strasbourg, France
3Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
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A Klein
1INSERM UMR S1109, Tumor Biomechanics, Strasbourg, France
2Université de Strasbourg, Strasbourg, France
3Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
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N Osmani
1INSERM UMR S1109, Tumor Biomechanics, Strasbourg, France
2Université de Strasbourg, Strasbourg, France
3Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
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I Busnelli
1INSERM UMR S1109, Tumor Biomechanics, Strasbourg, France
2Université de Strasbourg, Strasbourg, France
3Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
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F Delalande
4Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), IPHC UMR 7178, CNRS, Université de Strasbourg, Strasbourg, France
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N Paul
1INSERM UMR S1109, Tumor Biomechanics, Strasbourg, France
2Université de Strasbourg, Strasbourg, France
3Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
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S Halary
5CNRS, UMR 7245 MCAM, Muséum National d’Histoire Naturelle de Paris, Paris, France
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F Gros
1INSERM UMR S1109, Tumor Biomechanics, Strasbourg, France
2Université de Strasbourg, Strasbourg, France
3Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
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L Fouillen
6Université de Bordeaux, CNRS, Laboratoire de Biogenèse Membranaire, UMR 5200, 33140, Villenave d’Ornon, France
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AM Haeberle
7Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, F-67000 Strasbourg, France
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C Royer
8Plateforme Imagerie In Vitro, CNRS UPS 3156, Strasbourg, France
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C Spiegelhalter
9IGBMC Imaging Center CNRS (UMR7104)/ INSERM (U1258)/ Université de Strasbourg, Illkirch, France
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G André-Grégoire
10Team SOAP, CRCINA, INSERM, CNRS, Université de Nantes, Université d’Angers, Nantes, France
11Integrated Center for Oncology, ICO, St-Herblain, France
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K Murphy
12The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia
13Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia
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P Timpson
12The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia
13Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney, New South Wales 2010, Australia
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R Carapito
1INSERM UMR S1109, Tumor Biomechanics, Strasbourg, France
2Université de Strasbourg, Strasbourg, France
3Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
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M Blot-Chabaud
14C2VN, INSERM 1263, Inrae 1260, Aix-Marseille Université, 27 Bd J. Moulin, 13005 Marseille, France
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J Gavard
10Team SOAP, CRCINA, INSERM, CNRS, Université de Nantes, Université d’Angers, Nantes, France
11Integrated Center for Oncology, ICO, St-Herblain, France
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C Carapito
4Laboratoire de Spectrométrie de Masse BioOrganique (LSMBO), IPHC UMR 7178, CNRS, Université de Strasbourg, Strasbourg, France
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N Vitale
7Centre National de la Recherche Scientifique, Université de Strasbourg, Institut des Neurosciences Cellulaires et Intégratives, F-67000 Strasbourg, France
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O Lefebvre
1INSERM UMR S1109, Tumor Biomechanics, Strasbourg, France
2Université de Strasbourg, Strasbourg, France
3Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
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  • ORCID record for O Lefebvre
JG Goetz
1INSERM UMR S1109, Tumor Biomechanics, Strasbourg, France
2Université de Strasbourg, Strasbourg, France
3Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
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  • For correspondence: hyenne@unistra.fr jacky.goetz@inserm.fr
V Hyenne
1INSERM UMR S1109, Tumor Biomechanics, Strasbourg, France
2Université de Strasbourg, Strasbourg, France
3Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
15CNRS SNC5055, Strasbourg, France
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  • ORCID record for V Hyenne
  • For correspondence: hyenne@unistra.fr jacky.goetz@inserm.fr
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Abstract

Cancer extracellular vesicles (EVs) mainly exert pro-tumoral functions by changing the phenotypes of stromal cells to the benefit of tumor growth and metastasis. They shuttle to distant organs and fertilize pre-metastatic niches facilitating subsequent seeding by circulating tumor cells. The levels of tumor secreted EVs correlate with tumor aggressiveness, however, the link between EV secretion mechanisms and their capacity to form pre-metastatic niches remains obscure. Here, we show that GTPases of the Ral family control, through the phospholipase D1, multi-vesicular bodies homeostasis and thereby tune the biogenesis and secretion of pro-metastatic EVs. RalA and RalB promote lung metastasis in a syngeneic mouse model. Importantly, EVs from RalA or RalB depleted cells have limited organotropic capacities in vivo and, as a consequence, are less efficient in promoting lung metastasis. RalA or RalB modulate the EV levels of the adhesion molecule MCAM/CD146, which mediates lung colonization. Finally, RalA and RalB, but also MCAM/CD146, are factors of poor prognosis in human breast cancer patients. Altogether, our study identifies Ral GTPases as central molecules linking the mechanisms of EVs secretion, cargo loading to their capacity to disseminate and induce pre-metastatic niches.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Ral GTPases promote metastasis by controlling biogenesis and organ colonization of exosomes
S Ghoroghi, B Mary, A Larnicol, A Klein, N Osmani, I Busnelli, F Delalande, N Paul, S Halary, F Gros, L Fouillen, AM Haeberle, C Royer, C Spiegelhalter, G André-Grégoire, K Murphy, P Timpson, R Carapito, M Blot-Chabaud, J Gavard, C Carapito, N Vitale, O Lefebvre, JG Goetz, V Hyenne
bioRxiv 2020.07.10.196691; doi: https://doi.org/10.1101/2020.07.10.196691
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Ral GTPases promote metastasis by controlling biogenesis and organ colonization of exosomes
S Ghoroghi, B Mary, A Larnicol, A Klein, N Osmani, I Busnelli, F Delalande, N Paul, S Halary, F Gros, L Fouillen, AM Haeberle, C Royer, C Spiegelhalter, G André-Grégoire, K Murphy, P Timpson, R Carapito, M Blot-Chabaud, J Gavard, C Carapito, N Vitale, O Lefebvre, JG Goetz, V Hyenne
bioRxiv 2020.07.10.196691; doi: https://doi.org/10.1101/2020.07.10.196691

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