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Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes

Shima Ghoroghi 1 Benjamin Mary 1 Annabel Larnicol 1 Nandini Asokan 1 Annick Klein 1 Nael Osmani 1 Ignacio Busnelli 1 François Delalande 2 Nicodème Paul 1 Sébastien Halary 3 Frédéric Gros 1 Laetitia Fouillen 4 Anne-Marie Haeberle 5 Cathy Royer 6 Coralie Spiegelhalter 7 Gwennan André-Grégoire 8 Vincent Mittelheisser 1 Alexandre Detappe 9 Kendelle Murphy 10 Paul Timpson 10 Raphaël Carapito 1 Marcel Blot-Chabaud 11 Julie Gavard 8 Christine Carapito 2 Nicolas Vitale 5 Olivier Lefebvre 1 Jacky G. Goetz 1 Vincent Hyenne 1
1 Immuno-Rhumatologie Moléculaire
2 DSA-IPHC - Département Sciences Analytiques et Interactions Ioniques et Biomoléculaires
3 MCAM - Molécules de Communication et Adaptation des Micro-organismes
4 LBM - Laboratoire de biogenèse membranaire
5 INCI - Institut des Neurosciences Cellulaires et Intégratives
6 Centre de Neurochimie
7 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire
8 CRCINA-ÉQUIPE 15 - Signaling in Oncogenesis, Angiogenesis and Permeability
CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers
9 ICANS - Institut de Cancérologie de Strasbourg Europe
10 The Garvan Institute of Medical Research [Sydney, Australia]
11 C2VN - Centre recherche en CardioVasculaire et Nutrition = Center for CardioVascular and Nutrition research
Abstract : Cancer extracellular vesicles (EVs) shuttle at distance and fertilize pre-metastatic niches facilitating subsequent seeding by tumor cells. However, the link between EV secretion mechanisms and their capacity to form pre-metastatic niches remains obscure. Using mouse models, we show that GTPases of the Ral family control, through the phospholipase D1, multi-vesicular bodies homeostasis and tune the biogenesis and secretion of pro-metastatic EVs. Importantly, EVs from RalA or RalB depleted cells have limited organotropic capacities in vivo and are less efficient in promoting metastasis. RalA and RalB reduce the EV levels of the adhesion molecule MCAM/CD146, which favors EV-mediated metastasis by allowing EVs targeting to the lungs. Finally, RalA, RalB and MCAM/CD146, are factors of poor prognosis in breast cancer patients. Altogether, our study identifies RalGTPases as central molecules linking the mechanisms of EVs secretion and cargo loading to their capacity to disseminate and induce pre-metastatic niches in a CD146 dependent manner.
Keywords : zebrafish mouse human cell biology cancer biology
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https://www.hal.inserm.fr/inserm-03103515
Contributor : Elizabeth Bernardo <>
Submitted on : Friday, January 8, 2021 - 10:56:54 AM
Last modification on : Wednesday, June 30, 2021 - 2:20:03 PM
Long-term archiving on: : Friday, April 9, 2021 - 6:36:48 PM

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INSERM | IGBMC | IN2P3 | IPHC | CRCINA | UNIV-NANTES | UNIV-AMU | MNHN | UNIV-ANGERS | CNRS | INRAE | SITE-ALSACE | DRS-IPHC | DSA-IPHC

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Shima Ghoroghi, Benjamin Mary, Annabel Larnicol, Nandini Asokan, Annick Klein, et al.. Ral GTPases promote breast cancer metastasis by controlling biogenesis and organ targeting of exosomes. eLife, eLife Sciences Publication, 2021, pp.e61539. ⟨10.7554/eLife.61539⟩. ⟨inserm-03103515⟩

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