Glioblastoma (GBM), the most common and severe type of brain cancer, are hierarchically organized with a small subpopulation of self-renewing highly tumorigenic cells, termed glioblastoma stem cells (GSCs), important for tumor initiation, continued growth, and resistance to therapies. GSCs reside in perivascular and hypoxic niches that support their survival and the maintenance of their stem-like state. Like all cancers, GBMs display the Warburg effect, a preferential utilization of aerobic glycolysis for energy supplies. Reliance upon aerobic glycolysis reduces cellular oxygen requirements yet is highly glucose inefficient and requires a steady glucose supply. How GSCs residing in the nutrient-poor hypoxic niche can supply their increased glucose demands amidst local glucose scarcity is poorly known. We have recently shown that GSCs preferentially uptake glucose compared to non-GSCs or normal cells through expression of the specialized, high-affinity glucose transporter isoform, type 3 (GLUT3). GLUT3 is expressed in very few other cell types, including embryonic stem (ES) cells, and non-stem GBM cells cultured in low glucose can de-differentiate, gain stem cell characteristics, and express the ES cell factor NANOG, correlating with survival. The goal of this research is to test the hypothesis that ES cell-like epigenetic reprogramming in GSCs allows resistance to extracellular metabolic stress, such as found in the hypoxic niche of tumors, through expression of the glucose transporter GLUT3.

Public Health Relevance

Glioblastoma is the most common and aggressive form of brain cancer and is notoriously chemotherapy- and radiation-resistant. These studies will shed light on how the cancer stem cells driving this cancer are able to survive despite significant metabolic stresses. If these studies confirm that glioblastoma stem cells require a rare and specialized glucose transporter to survive in living tumors, this could open an avenue to therapeutics able to destroy the cancer stem cells without affecting the normal tissues of a patient.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Mcguirl, Michele
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Cleveland Clinic Lerner
Other Basic Sciences
Schools of Medicine
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Miller, Tyler E; Liau, Brian B; Wallace, Lisa C et al. (2017) Transcription elongation factors represent in vivo cancer dependencies in glioblastoma. Nature 547:355-359
Mack, Stephen C; Hubert, Christopher G; Miller, Tyler E et al. (2016) An epigenetic gateway to brain tumor cell identity. Nat Neurosci 19:10-9
Hubert, Christopher G; Rivera, Maricruz; Spangler, Lisa C et al. (2016) A Three-Dimensional Organoid Culture System Derived from Human Glioblastomas Recapitulates the Hypoxic Gradients and Cancer Stem Cell Heterogeneity of Tumors Found In Vivo. Cancer Res 76:2465-77
Schonberg, David L; Miller, Tyler E; Wu, Qiulian et al. (2015) Preferential Iron Trafficking Characterizes Glioblastoma Stem-like Cells. Cancer Cell 28:441-455