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Brain cancer cells coexist with the glial cells in a functional syncytium based on a continuous metabolic rewiring. However, standard glioma therapies do not account for the effects of the glial cells within the tumor microenvironment. This may be a possible reason for the lack of improvements in patients with high-grade gliomas therapies. Cell metabolism and bioenergetic fitness depend on the availability of nutrients and interactions in the microenvironment. It is strictly related to the cell location in the tumor mass, proximity to blood vessels, biochemical gradients, and tumor evolution, underlying the influence of the context and the timeline in anti-tumor therapeutic approaches. Besides the cancer metabolic strategies, here we review the modifications found in the GBM-associated glia, focusing on morphological, molecular, and metabolic features. We propose to analyze the GBM metabolic rewiring processes from a systems biology perspective. We aim at defining the crosstalk between GBM and the glial cells as modules. The complex networking may be expressed by metabolic modules corresponding to the GBM growth and spreading phases. Variation in the oxidative phosphorylation (OXPHOS) rate and regulation appears to be the most important part of the metabolic and functional heterogeneity, correlating with glycolysis and response to hypoxia. Integrated metabolic modules along with molecular and morphological features could allow the identification of key factors for controlling the GBM-stroma metabolism in multi-targeted, time-dependent therapies.<\/jats:p>","DOI":"10.3390\/ijms22073301","type":"journal-article","created":{"date-parts":[[2021,3,24]],"date-time":"2021-03-24T15:42:19Z","timestamp":1616600539000},"page":"3301","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["The Glioblastoma Microenvironment: Morphology, Metabolism, and Molecular Signature of Glial Dynamics to Discover Metabolic Rewiring Sequence"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5304-247X","authenticated-orcid":false,"given":"Assunta","family":"Virtuoso","sequence":"first","affiliation":[{"name":"Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania \u2018\u2018Luigi Vanvitelli\u201d, 80138 Naples, Italy"},{"name":"School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7706-0672","authenticated-orcid":false,"given":"Roberto","family":"Giovannoni","sequence":"additional","affiliation":[{"name":"Department of Biology, University of Pisa, 56126 Pisa, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8146-5736","authenticated-orcid":false,"given":"Ciro","family":"De Luca","sequence":"additional","affiliation":[{"name":"Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania \u2018\u2018Luigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Gargano","sequence":"additional","affiliation":[{"name":"Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania \u2018\u2018Luigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michele","family":"Cerasuolo","sequence":"additional","affiliation":[{"name":"Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania \u2018\u2018Luigi Vanvitelli\u201d, 80138 Naples, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicola","family":"Maggio","sequence":"additional","affiliation":[{"name":"Department of Neurology, Sackler Faculty of Medicine, Sagol School of Neuroscience, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"Department of Neurology, The Chaim Sheba Medical Center, Ramat Gan 5211401, Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4852-1318","authenticated-orcid":false,"given":"Marialuisa","family":"Lavitrano","sequence":"additional","affiliation":[{"name":"School of Medicine and Surgery, University of Milano-Bicocca, 20900 Monza, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6609-7453","authenticated-orcid":false,"given":"Michele","family":"Papa","sequence":"additional","affiliation":[{"name":"Laboratory of Neuronal Networks, Department of Mental and Physical Health and Preventive Medicine, University of Campania \u2018\u2018Luigi Vanvitelli\u201d, 80138 Naples, Italy"},{"name":"SYSBIO Centre of Systems Biology ISBE-IT, University of Milano-Bicocca, 20126 Milan, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1111\/nan.12432","article-title":"WHO 2016 Classification of gliomas","volume":"44","author":"Wesseling","year":"2018","journal-title":"Neuropathol. 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