Specific V-ATPase expression sub-classifies IDHwt lower-grade gliomas and impacts glioma growth in vivo

Andrea Terrasi, Irene Bertolini, Cristina Martelli, Gabriella Gaudioso, Andrea Di Cristofori, Alessandra Maria Storaci, Miriam Formica, Silvano Bosari, Manuela Caroli, Luisa Ottobrini, Thomas Vaccari, Valentina Vaira

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Cancer cells use specific V-ATPase subunits to activate oncogenic pathways. Therefore, we investigated V-ATPase deregulation in aggressive gliomas and associated signaling. Methods: V-ATPase genes expression and associated pathways were analyzed in different series of glioma available from public databases, as well as in patients’ cohort. Activation of pathways was analyzed at gene and protein expression levels. A genetic model of glioma in Drosophila melanogaster and mice with GBM patients-derived orthotopic xenografts were used as in vivo models of disease. Findings: GBM and recurrent gliomas display a specific V-ATPase signature. Such signature resolves the heterogeneous class of IDH-wild type lower-grade gliomas, identifying the patients with worse prognosis independently from clinical and molecular features (p = 0·03, by Cox proportional-hazards model). In vivo, V-ATPase subunits deregulation significantly impacts tumor growth and proliferation. At the molecular level, GBM-like V-ATPase expression correlates with upregulation of Homeobox genes. Interpretation: Our data identify a V-ATPase signature that accompanies glioma aggressiveness and suggest new entry points for glioma stratification and follow-up. Fund: This work was supported by Fondazione Cariplo (2014–1148 to VV), Fondazione IRCCS Ca’ Granda, and Fondazione INGM Grant in Molecular Medicine 2014 (to VV).

Original languageEnglish
Pages (from-to)214-224
Number of pages11
JournalEBioMedicine
Volume41
DOIs
Publication statusPublished - Mar 1 2019

Keywords

  • Glioma stem cells
  • Homeobox genes
  • IDHwt/lower-grade glioma
  • V-ATPase

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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