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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| Format: | Article |
| Language: | English |
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BMC
2025-01-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-025-03280-3 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Alessandra Maria Storaci |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-e24fa5a63d0045a6ad95fd0b22e728db |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-e24fa5a63d0045a6ad95fd0b22e728db2025-01-19T12:43:19ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662025-01-0144111410.1186/s13046-025-03280-3V-ATPase in glioma stem cells: a novel metabolic vulnerabilityAlessandra Maria Storaci0Irene Bertolini1Cristina Martelli2Giorgia De Turris3Nadia Mansour4Mariacristina Crosti5Maria Rosaria De Filippo6Luisa Ottobrini7Luca Valenti8Elisa Polledri9Silvia Fustinoni10Manuela Caroli11Claudia Fanizzi12Silvano Bosari13Stefano Ferrero14Giorgia Zadra15Valentina Vaira16Department of Pathophysiology and Transplantation, University of MilanMolecular and Cellular Oncogenesis Program, Wistar InstituteDepartment of Pathophysiology and Transplantation, University of MilanDepartment of Pathophysiology and Transplantation, University of MilanDivision of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoINGM, Istituto Nazionale Di Genetica Molecolare “Romeo Ed Enrica Invernizzi”Division of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoDepartment of Pathophysiology and Transplantation, University of MilanDepartment of Pathophysiology and Transplantation, University of MilanEPIGET-Epidemiology, Epigenetics, and Toxicology Lab, Department of Clinical Sciences and Community Health, University of MilanEPIGET-Epidemiology, Epigenetics, and Toxicology Lab, Department of Clinical Sciences and Community Health, University of MilanDivision of Neurosurgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoDivision of Neurosurgery, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoDepartment of Pathophysiology and Transplantation, University of MilanDivision of Pathology, Fondazione IRCCS Ca’ Granda Ospedale Maggiore PoliclinicoInstitute of Molecular Genetics, National Research Council (CNR-IGM)Department of Pathophysiology and Transplantation, University of MilanAbstract 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.https://doi.org/10.1186/s13046-025-03280-3GliomaGlioma stem cellV-ATPaseMetabolismBafilomycin A1 |
| spellingShingle | 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 V-ATPase in glioma stem cells: a novel metabolic vulnerability Journal of Experimental & Clinical Cancer Research Glioma Glioma stem cell V-ATPase Metabolism Bafilomycin A1 |
| title | V-ATPase in glioma stem cells: a novel metabolic vulnerability |
| title_full | V-ATPase in glioma stem cells: a novel metabolic vulnerability |
| title_fullStr | V-ATPase in glioma stem cells: a novel metabolic vulnerability |
| title_full_unstemmed | V-ATPase in glioma stem cells: a novel metabolic vulnerability |
| title_short | V-ATPase in glioma stem cells: a novel metabolic vulnerability |
| title_sort | v atpase in glioma stem cells a novel metabolic vulnerability |
| topic | Glioma Glioma stem cell V-ATPase Metabolism Bafilomycin A1 |
| url | https://doi.org/10.1186/s13046-025-03280-3 |
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