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).

Specific V-ATPase expression sub-classifies IDHwt lower-grade gliomas and impacts glioma growth in vivo / A. Terrasi, I. Bertolini, C. Martelli, G. Gaudioso, A. Di Cristofori, A.M. Storaci, M. Formica, S. Bosari, M. Caroli, L. Ottobrini, T. Vaccari, V. Vaira. - In: EBIOMEDICINE. - ISSN 2352-3964. - 41(2019 Mar), pp. 214-224. [10.1016/j.ebiom.2019.01.052]

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

A. Terrasi
Co-primo
;
I. Bertolini
Co-primo
;
C. Martelli;G. Gaudioso;A. Di Cristofori;A.M. Storaci;M. Formica;S. Bosari;L. Ottobrini;T. Vaccari
Penultimo
;
V. Vaira
Ultimo
2019

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).
Glioma stem cells; Homeobox genes; IDHwt/lower-grade glioma; V-ATPase; Biochemistry, Genetics and Molecular Biology (all)
Settore BIO/13 - Biologia Applicata
Settore MED/08 - Anatomia Patologica
   The functional importance of V-ATPase upregulation in human gliomas
   FONDAZIONE CARIPLO
   2014-1148

   Systematic genetic and pharmacologic modulation of Notch signaling and tumorigenesis in human cells and Drosophila (2º anno)
   FONDAZIONE AIRC PER LA RICERCA SUL CANCRO ETS
   IG 2017 ID. 20661
mar-2019
5-mar-2019
Article (author)
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2434/625375
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