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A GBM-like V-ATPase signature directs cell-cell tumor signaling and reprogramming via large oncosomes.
Bertolini, Irene; Terrasi, Andrea; Martelli, Cristina; Gaudioso, Gabriella; Di Cristofori, Andrea; Storaci, Alessandra Maria; Formica, Miriam; Braidotti, Paola; Todoerti, Katia; Ferrero, Stefano; Caroli, Manuela; Ottobrini, Luisa; Vaccari, Thomas; Vaira, Valentina.
Afiliação
  • Bertolini I; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Terrasi A; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Martelli C; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
  • Gaudioso G; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Di Cristofori A; Division of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Storaci AM; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
  • Formica M; Department of Biosciences, Universita' degli Studi di Milano, Milan, Italy.
  • Braidotti P; Division of Pathology, San Paolo Hospital, Milan, Italy.
  • Todoerti K; Department of Oncology and Hemato-oncology, University of Milan, Hematology Division, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Ferrero S; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Biosciences, University of Milan, Milan, Italy.
  • Caroli M; Division of Neurosurgery, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
  • Ottobrini L; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy.
  • Vaccari T; Department of Biosciences, University of Milan, Milan, Italy. Electronic address: thomas.vaccari@unimi.it.
  • Vaira V; Division of Pathology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; Fondazione Istituto Nazionale Genetica Molecolare 'Romeo ed Enrica Invernizzi', Milan, Italy. Electronic
EBioMedicine ; 41: 225-235, 2019 Mar.
Article em En | MEDLINE | ID: mdl-30737083
ABSTRACT

BACKGROUND:

The V-ATPase proton pump controls acidification of intra and extra-cellular milieu in both physiological and pathological conditions. We previously showed that some V-ATPase subunits are enriched in glioma stem cells and in patients with poor survival. In this study, we investigated how expression of a GBM-like V-ATPase pump influences the non-neoplastic brain microenvironment.

METHODS:

Large oncosome (LO) vesicles were isolated from primary glioblastoma (GBM) neurospheres, or from patient sera, and co-cultured with primary neoplastic or non-neoplastic brain cells. LO transcript and protein contents were analyzed by qPCR, immunoblotting and immunogold staining. Activation of pathways in recipient cells was determined at gene and protein expression levels. V-ATPase activity was impaired by Bafilomycin A1 or gene silencing.

FINDINGS:

GBM neurospheres influence their non-neoplastic microenvironment by delivering the V-ATPase subunit V1G1 and the homeobox genes HOXA7, HOXA10, and POU3F2 to recipient cells via LO. LOs reprogram recipient cells to proliferate, grow as spheres and to migrate. Moreover, LOs are particularly abundant in the circulation of GBM patients with short survival time. Finally, impairment of V-ATPase reduces LOs activity.

INTERPRETATION:

We identified a novel mechanism adopted by glioma stem cells to promote disease progression via LO-mediated reprogramming of their microenvironment. Our data provide preliminary evidence for future development of LO-based liquid biopsies and suggest a novel potential strategy to contrast glioma progression. FUND This work was supported by Fondazione Cariplo (2014-1148 to VV) and by the Italian Minister of Health-Ricerca Corrente program 2017 (to SF).
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Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Glioblastoma / Comunicação Autócrina / ATPases Vacuolares Próton-Translocadoras / Micropartículas Derivadas de Células Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: EBioMedicine Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Itália

Texto completo: 1 Bases de dados: MEDLINE Assunto principal: Neoplasias Encefálicas / Glioblastoma / Comunicação Autócrina / ATPases Vacuolares Próton-Translocadoras / Micropartículas Derivadas de Células Tipo de estudo: Prognostic_studies Limite: Animals / Humans Idioma: En Revista: EBioMedicine Ano de publicação: 2019 Tipo de documento: Article País de afiliação: Itália