The brain is one of the most metabolically active organs with glucose representing the most important, but not the only, source of energy and carbon. Like all cancers, glioblastoma, the most prevalent and malignant primary brain tumor, requires a continuous source of energy and molecular resources for new cell production with a preferential use of aerobic glycolysis, recognized as the Warburg effect. Aerobic glycolysis diminishes the need for oxygen, while inefficient liberation of energy permits residual carbons to be shunted to produce cellular components. Glioblastoma is a highly lethal cancer type with almost all targeted therapeutics tested to date showing minimal to no sustained clinical benefit. The failure to achieve cure has many causes, but we and others have linked self-renewing, highly tumorigenic glioma stem cells (GSCs) to therapeutic resistance, invasion into normal tissues, and increased angiogenesis. Targeting GSCs can inhibit tumor growth and sensitize tumors to conventional therapies. In this application, two leading GSC laboratories with complementary research foci have joined forces to examine the relationship between GSCs and metabolism. Isocitrate dehydrogenase 1 (IDH1) mutations directly link transformation and metabolism in low grade gliomas and secondary glioblastoma, but these mutations are relatively rare in glioblastoma, suggesting that alternative metabolic alterations are likely present. Our two groups have interrogated GSC glucose metabolism within the cellular hierarchy (intratumoral heterogeneity) and between tumors (intertumoral heterogeneity). In preliminary studies, we found that nutrient restriction mimicking tumor conditions enriches for GSCs through preferential GSC survival and acquisition of stem- like features in differentiated cells. GSCs respond to low glucose by preferential uptake of glucose through the expression of a specialized, high affinity neuronal glucose transporter (Glut3). Glut3 enriches for GSCs and targeting Glut3 expression attenuates stem cell self-renewal and tumor growth. GSCs are not static, but rather evolve during treatment. GSCs from proneural and mesenchymal glioblastomas display differential gene expression profiles and radiation sensitivity with increased glycolytic activity in mesenchymal GSCs. Radiation induces a proneural-to-mesenchymal transition associated with activation of glycolytic metabolism and aldehyde dehydrogenase activity. As selected metabolic nodes are amenable to therapeutic targeting, we hypothesize that the Warburg effect causally contributes to glioma heterogeneity through cellular hierarchical and clonal evolution mechanisms. In this application, the first aim will determine the tumor microenvironment reprograms glucose uptake to instruct glioblastoma cellular hierarchies. As an independent yet complementary study, the second aim will determine the role of glycolytic reprogramming in the evolution of glioma stem cells to acquire therapeutic resistance. The ultimate goals of these studies are to establish a new concept by incorporating both the cellular hierarchical theory and the clonal evolution theory to better clarify the mechanism of tumor heterogeneity and to establish targeted therapies for distinct molecules that are responsible for a gain of resistance t current therapies. The proposed studies, when completed, will challenge the current research and clinical practice hurdles and will create a firm path to translation by developing a novel strategy to target the newly identified metabolic alterations in glioblastomas.

Public Health Relevance

Glioblastomas are deadly cancers that are resistant to currently used therapies supporting the urgent need for new treatments. Glioblastomas, like many cancers, contain cells that share similarities with normal stem cells and display resistance to radiation and chemotherapy supporting the concept of these so called cancer stem cells as possible targets. We are investigating the role of cellular metabolism in the growth and resistance of glioblastoma cancer stem cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
1R01NS087913-01
Application #
8722074
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Fountain, Jane W
Project Start
2014-04-15
Project End
2019-02-28
Budget Start
2014-04-15
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Mack, Stephen C; Pajtler, Kristian W; Chavez, Lukas et al. (2018) Therapeutic targeting of ependymoma as informed by oncogenic enhancer profiling. Nature 553:101-105
Sadahiro, Hirokazu; Kang, Kyung-Don; Gibson, Justin T et al. (2018) Activation of the Receptor Tyrosine Kinase AXL Regulates the Immune Microenvironment in Glioblastoma. Cancer Res 78:3002-3013
Pavlyukov, Marat S; Yu, Hai; Bastola, Soniya et al. (2018) Apoptotic Cell-Derived Extracellular Vesicles Promote Malignancy of Glioblastoma Via Intercellular Transfer of Splicing Factors. Cancer Cell 34:119-135.e10
Wang, Xiuxing; Prager, Briana C; Wu, Qiulian et al. (2018) Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression. Cell Stem Cell 22:514-528.e5
Zhu, Zhe; Gorman, Matthew J; McKenzie, Lisa D et al. (2017) Zika virus has oncolytic activity against glioblastoma stem cells. J Exp Med 214:2843-2857
Jung, Jinkyu; Kim, Leo J Y; Wang, Xiuxing et al. (2017) Nicotinamide metabolism regulates glioblastoma stem cell maintenance. JCI Insight 2:
Wang, Xiuxing; Yang, Kailin; Xie, Qi et al. (2017) Purine synthesis promotes maintenance of brain tumor initiating cells in glioma. Nat Neurosci 20:661-673
Wang, Jia; Cheng, Peng; Pavlyukov, Marat S et al. (2017) Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2. J Clin Invest 127:3075-3089
Wang, Xiuxing; Huang, Zhi; Wu, Qiulian et al. (2017) MYC-Regulated Mevalonate Metabolism Maintains Brain Tumor-Initiating Cells. Cancer Res 77:4947-4960
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

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