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Background <p>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.</p> Methods <p>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.</p> Results <p>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.</p> Conclusions <p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月17日

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  • 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

摘要

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.