Beyond the Warburg Effect: A Study of Metabolic Alterations in Malignancies of the Posterior Fossa
Dang, Derek
2024
Abstract
Central nervous system malignancies are considered highly devastating across both adult and pediatric populations. These cancers frequently originate in regions of the brain where surgery is not feasible, exhibit resistance to standard chemotherapy and radiation treatments, and are devoid of effective therapeutic alternatives. Unlike their counterparts in adults, pediatric brain tumors are less likely to contain recurrent genetic mutations. Therefore, finding new targeted treatments for these tumors remains especially challenging. In this dissertation, I seek to understand how two pediatric CNS malignancies, Group A posterior fossa ependymomas and Group 3 medulloblastomas, exhibit ectopic expression of genes that fundamentally rewire and fuel their metabolic needs. Deregulation of cellular metabolism is a well-documented hallmark of cancer. Otto Warburg first described a phenomenon called aerobic glycolysis, where cells preferentially generate ATP through lactate fermentation even when mitochondrial function and oxygen levels are normal. However, in the following chapters, I will demonstrate that oncogenic-driven metabolic rewiring in Group A posterior fossa ependymomas and Group 3 medulloblastomas also results in enhanced non-glycolytic metabolism which is also essential for tumor pathogenesis. In Chapter 1, I present a comprehensive review of ependymomas and medulloblastomas and discuss their defining genetic and molecular features, current subgroupings, and existing therapeutic options. This chapter also summarizes current knowledge regarding epigenetic alterations in posterior fossa malignancies, including key protein complexes that induce changes in DNA and histone methylation that drive tumor growth. I conclude this chapter by discussing relevant aspects of cancer metabolism that fuel the energy and macromolecule needs of posterior fossa malignancies. In Chapter 2, I show my findings regarding the role of EZH2-inhibitory protein (EZHIP) in the epigenetic alteration of metabolism in Group A posterior fossa ependymomas (PFA). I first show that PFA exhibit enhanced glycolysis and TCA-cycle metabolism compared to non-EZHIP-expressing Group B posterior fossa ependymoma. Then, I show that EZHIP expression is significantly correlated with high H3K27ac, PFA location, and poor prognosis. I demonstrate that EZHIP expression alone in a neuronal stem cell model increases H3K27ac at key metabolic genes and enhances glycolytic and TCA-cycle metabolism. Finally, I show that metformin increases global histone hypermethylation and inhibits TCA-cycle metabolism in cell models and slows tumor growth in vivo, providing a new therapeutic option for PFA. In Chapter 3, I explore metabolic alterations unique to Group 3 medulloblastomas (MB). I demonstrate that MYC-amplified Group 3 MB have enhanced TCA-cycle and oxidative phosphorylation metabolism compared to other MB subtypes. I show unique upregulation of DLAT, the E2 component of the pyruvate dehydrogenases, in these tumors and demonstrate that DLAT is essential for increased glutathione and mitochondrial metabolism. Inhibition of IDH1 decreases MYC and DLAT levels and inhibits proliferation in Group 3 MB cell lines. Finally, I show that these tumors are sensitive to copper ionophore elesclomol, which induces cuproptosis and provides a viable therapeutic option in in vivo models. Chapter 4 summarizes my findings, discusses unexpected outcomes, and propose future experiments. Specifically, I begin by summarizing overall findings and identifying the commonalities that unite the two studies presented in this dissertation. I then discuss the unexpected finding of IDH1 as a regulator of MYC. I outline future experiments that aim to understand metabolism in the potential cell-of-origin of Group 3 MB. Finally, I discuss a potential mechanism that underlies EZHIP decrease upon metformin treatment.Deep Blue DOI
Subjects
Cancer Metabolism Cancer Epigenetics Cancer Ependymoma Medulloblastoma Neurooncology
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