An Experimentally Defined Hypoxia Gene Signature in Glioblastoma and Its Modulation by Metformin
Marta Calvo Tardón,
Eliana Marinari,
Denis Migliorini,
Viviane Bes,
Stoyan Tankov,
Emily Charrier,
Thomas A McKee,
Valérie Dutoit,
Pierre-Yves Dietrich,
Erika Cosset,
Paul R Walker
Affiliations
Marta Calvo Tardón
Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland
Eliana Marinari
Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland
Denis Migliorini
Department of Oncology, Clinical Research Unit, Dubois Ferrière Dinu Lipatti Research Foundation, Geneva University Hospitals, 1205 Geneva, Switzerland
Viviane Bes
Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland
Stoyan Tankov
Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland
Emily Charrier
Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland
Thomas A McKee
Division of Clinical Pathology, Geneva University Hospitals, 1211 Geneva, Switzerland
Valérie Dutoit
Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland
Pierre-Yves Dietrich
Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland
Erika Cosset
Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland
Paul R Walker
Center for Translational Research in Onco-Hematology, Division of Oncology, Geneva University Hospitals and University of Geneva, 1211 Geneva, Switzerland
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor, characterized by a high degree of intertumoral heterogeneity. However, a common feature of the GBM microenvironment is hypoxia, which can promote radio- and chemotherapy resistance, immunosuppression, angiogenesis, and stemness. We experimentally defined common GBM adaptations to physiologically relevant oxygen gradients, and we assessed their modulation by the metabolic drug metformin. We directly exposed human GBM cell lines to hypoxia (1% O2) and to physioxia (5% O2). We then performed transcriptional profiling and compared our in vitro findings to predicted hypoxic areas in vivo using in silico analyses. We observed a heterogenous hypoxia response, but also a common gene signature that was induced by a physiologically relevant change in oxygenation from 5% O2 to 1% O2. In silico analyses showed that this hypoxia signature was highly correlated with a perinecrotic localization in GBM tumors, expression of certain glycolytic and immune-related genes, and poor prognosis of GBM patients. Metformin treatment of GBM cell lines under hypoxia and physioxia reduced viable cell number, oxygen consumption rate, and partially reversed the hypoxia gene signature, supporting further exploration of targeting tumor metabolism as a treatment component for hypoxic GBM.
