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. 2022 Oct 19;10:1007641. doi: 10.3389/fcell.2022.1007641

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Copyright © 2022 Marabitti, Giansanti, De Mitri, Gatto, Mastronuzzi and Nazio.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Schematic representation of the impact of hypoxia-associated metabolic adaptation in MB. Hypoxia is a major component of the tumor microenvironment that shapes tumor heterogeneity; the levels of oxygen in cancer cells decrease with increasing distance from the blood vessels. In hypoxic MB cells, hypoxia-inducible factor 1 alpha (HIF1α) supports the Warburg effect by upregulating the expression of genes involved in the glycolytic pathway, such as GLUT1, carbonic anhydrase IX (CAIX) and pyruvate dehydrogenase kinase 1 (PDK1). The use of PDK1 inhibitor OSU03012 induces mitochondrial-dependent apoptosis in MB. Moreover, hypoxic conditions were found to trigger upregulation of NOTCH, which correlates with a poor prognosis in MB. A connection between HIF1α and NOTCH signaling is also found, driving stemness and cancer stem cells (CSCs) expansion. Finally, hypoxia upregulates CD133 (staminal marker) expression in MB cells and contributes to therapy resistance (after both etoposide (Eto) and radiotherapy (X-ray) treatments) by attenuating DNA damage signaling. Figure is created in “BioRender.com”.