Pharmacological targeting of apelin impairs glioblastoma growth

Elizabeth Harford-Wright; Gwennan André-Grégoire; Kathryn Jacobs; Lucas Treps; Sophie Le Gonidec; Héloïse Leclair; Sara Gonzalez-Diest; Quentin Roux; François Guillonneau; Delphine Loussouarn; Lisa Oliver; François Vallette; Fabienne Foufelle; Philippe Valet; Anthony Davenport; Robert Glen; Nicolas Bidere; Julie Gavard

doi:10.17863/CAM.12121

Journal articles

Pharmacological targeting of apelin impairs glioblastoma growth

Elizabeth Harford-Wright ^{1, 2} Gwennan André-Grégoire ¹ Kathryn Jacobs ¹ Lucas Treps ² Sophie Le Gonidec ³ Héloïse Leclair ^{2, 1} Sara Gonzalez-Diest ^{1, 2} Quentin Roux ¹ François Guillonneau ⁴ Delphine Loussouarn ⁵ Lisa Oliver ⁵ François Vallette ^{5, 6} Fabienne Foufelle ⁷ Philippe Valet ³ Anthony Davenport ⁸ Robert Glen ^{9, 10} Nicolas Bidere ^{1, 2} Julie Gavard ^{1, 2, *}

* Corresponding author

1 CRCINA-ÉQUIPE 15 - Signaling in Oncogenesis, Angiogenesis and Permeability

CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers

2 IC UM3 (UMR 8104 / U1016) - Institut Cochin

3 I2MC - Institut des Maladies Métaboliques et Cardiovasculaires

4 3P5 - Plateforme protéomique 3P5 [Institut Cochin]

IC UM3 (UMR 8104 / U1016) - Institut Cochin

5 CRCINA-ÉQUIPE 9 - Apoptosis and Tumor Progression

CRCINA - Centre de Recherche en Cancérologie et Immunologie Nantes-Angers

6 UNICANCER/ICO - Institut de Cancérologie de l'Ouest [Angers/Nantes]

7 CRC - Inserm U1138 - Pathogenèse cellulaire et clinique du diabète

CRC - Centre de Recherche des Cordeliers

8 Experimental Medicine and Immunotherapeutics [Cambridge, UK]

9 The Unilever Centre for Molecular Science Informatics - Department of Chemistry [Cambridge, UK]

10 Division of Computational and Systems Medicine - Department of Surgery and Cancer [London, UK]

Abstract : Glioblastoma are highly aggressive brain tumours that are associated with an extremely poor prognosis. Within these tumours exists a subpopulation of highly plastic self-renewing cancer cells that retain the ability to expand ex vivo as tumourspheres, induce tumour growth in mice, and have been implicated in radio-and chemo-resistance. Although their identity and fate are regulated by external cues emanating from endothelial cells, the nature of such signals remains unknown. Here, we used a mass spectrometry proteomic approach to characterize the factors released by brain endothelial cells. We report the identification of the vasoactive peptide apelin as a central regulator for endothelial-mediated maintenance of glioblastoma patient-derived cells with stem-like properties. Genetic and pharmacological targeting of apelin cognate receptor abrogates apelin-and endothelial-mediated expansion of glioblastoma patient-derived cells with stem-like properties in vitro and suppresses tumour growth in vivo. Functionally, selective competitive antagonists of apelin receptor were shown to be safe and effective in reducing tumour expansion and lengthening the survival of intracranially xenografted mice. Therefore, the apelin/apelin receptor signalling nexus may operate as a paracrine signal that sustains tumour cell expansion and progression, suggesting that apelin is a druggable factor in glioblastoma.

Keywords : vascular niche antagonist APJ apelin glioblastoma initiating cells

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Journal articles

Domain :

Life Sciences [q-bio] / Cancer

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https://www.hal.inserm.fr/inserm-01611131
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Submitted on : Thursday, October 5, 2017 - 3:21:00 PM
Last modification on : Friday, September 18, 2020 - 2:35:01 PM

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