V-ATPase in glioma stem cells: a novel metabolic vulnerability

V-ATPase in glioma stem cells: a novel metabolic vulnerability

Abstract Background Glioblastoma (GBM) is a lethal brain tumor characterized by the glioma stem cell (GSC) niche. The V-ATPase proton pump has been described as a crucial factor in sustaining GSC viability and tumorigenicity. Here we studied how patients-derived GSCs rely on V-ATPase activity to sus...

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Main Authors: Alessandra Maria Storaci, Irene Bertolini, Cristina Martelli, Giorgia De Turris, Nadia Mansour, Mariacristina Crosti, Maria Rosaria De Filippo, Luisa Ottobrini, Luca Valenti, Elisa Polledri, Silvia Fustinoni, Manuela Caroli, Claudia Fanizzi, Silvano Bosari, Stefano Ferrero, Giorgia Zadra, Valentina Vaira
Format: Article
Language:English
Published: BMC 2025-01-01
Series:Journal of Experimental & Clinical Cancer Research
Subjects:
Glioma
Glioma stem cell
V-ATPase
Metabolism
Bafilomycin A1
Online Access:https://doi.org/10.1186/s13046-025-03280-3
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Summary:Abstract Background Glioblastoma (GBM) is a lethal brain tumor characterized by the glioma stem cell (GSC) niche. The V-ATPase proton pump has been described as a crucial factor in sustaining GSC viability and tumorigenicity. Here we studied how patients-derived GSCs rely on V-ATPase activity to sustain mitochondrial bioenergetics and cell growth. Methods V-ATPase activity in GSC cultures was modulated using Bafilomycin A1 (BafA1) and cell viability and metabolic traits were analyzed using live assays. The GBM patients-derived orthotopic xenografts were used as in vivo models of disease. Cell extracts, proximity-ligation assay and advanced microscopy was used to analyze subcellular presence of proteins. A metabolomic screening was performed using Biocrates p180 kit, whereas transcriptomic analysis was performed using Nanostring panels. Results Perturbation of V-ATPase activity reduces GSC growth in vitro and in vivo. In GSC there is a pool of V-ATPase that localize in mitochondria. At the functional level, V-ATPase inhibition in GSC induces ROS production, mitochondrial damage, while hindering mitochondrial oxidative phosphorylation and reducing protein synthesis. This metabolic rewiring is accompanied by a higher glycolytic rate and intracellular lactate accumulation, which is not exploited by GSCs for biosynthetic or survival purposes. Conclusions V-ATPase activity in GSC is critical for mitochondrial metabolism and cell growth. Targeting V-ATPase activity may be a novel potential vulnerability for glioblastoma treatment.
ISSN:1756-9966

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