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Endothelial apelin employs APJ and GP130 to sustain glioblastoma stem cells

Eva M Galan-Moya1,2,3, Lucas Treps1,2,3, Elizabeth Harford-Wright1,2,3, Sophie Le Gonidec4, Héloïse M Leclair1,2,3, Armelle Le Guelte1,2,3, Julie Dwyer1,2,3, Sonia M Dubois1,2,3, Ralf Jockers1,2,3, François Guillonneau3,5, Delphine Loussouam6, Lisa Oliver6,7, François M Vallette6,7, Philippe Valet4, Anthony P Davenport8, Robert C Glen9,10, Nicolas Bidère1,2,3, and Julie Gavard1,2,3,*

Glioblastoma are deadly brain tumours that contain a subpopulation of highly plastic self-renewing cancer cells 1. These so-called glioblastoma stem-like cells (GSCs) retain the ability to expand ex vivo as tumourspheres and recapitulate tumour ontogenesis in mice, whilst they sustain radio- and chemo-resistance 2,3. Although their survival is regulated by external cues emanating from endothelial cells 4,5, the nature of such angiocrine signals is still unknown. Here, we deployed a mass spectrometry proteomic approach to characterise the factors released by brain endothelial cells. We report the identification of apelin as a central regulator for endothelial-mediated self-renewal and survival in patient-derived GSCs. Genetic and pharmacological targeting of apelin cognate receptor APJ abrogates apelin- and endothelial-mediated pro-survival effects on GSCs and quells tumour initiation and growth. Molecularly, the cytokine co-receptor GP130 was strictly required for apelin- and endothelial-governed actions, as it maintains APJ at the plasma membrane. The APLN/APJ/GP130 signalling nexus might thus operate as a niche-specific signal that sustains tumour initiation and progression, suggesting that apelin is a druggable paracrine factor in glioblastoma.

Format: Oral communication

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