Metabolic Rewiring in Glioblastoma Cancer: EGFR, IDH and Beyond

Abstract

Glioblastoma multiforme (GBM), a highly invasive and incurable tumor, is the humans' foremost, commonest, and deadliest brain cancer. As in other cancers, distinct combinations of genetic alterations (GA) in GBM induce a diversity of metabolic phenotypes resulting in enhanced malignancy and altered sensitivity to current therapies. Furthermore, GA as a hallmark of cancer, dysregulated cell metabolism in GBM has been recently linked to the acquired GA. Indeed, Numerous point mutations and copy number variations have been shown to drive glioma cells' metabolic state, affecting tumor growth and patient outcomes. Among the most common, IDH mutations, EGFR amplification, mutation, PTEN loss, and MGMT promoter mutation have emerged as key patterns associated with upregulated glycolysis and OXPHOS glutamine addiction and altered lipid metabolism in GBM. Therefore, current Advances in cancer genetic and metabolic profiling have yielded mechanistic insights into the metabolism rewiring of GBM and provided potential avenues for improved therapeutic modalities. Accordingly, actionable metabolic dependencies are currently used to design new treatments for patients with glioblastoma. Herein, we capture the current knowledge of genetic alterations in GBM, provide a detailed understanding of the alterations in metabolic pathways, and discuss their relevance in GBM therapy.

Keywords: GBM; genetic alteration; glioma therapy; glycolysis; metabolic genes.

Figure 1

Commonly mutated genes and copy number variations in GBMs. Data (592 patients) from the TCGA dataset (Glioblastoma multiforme; TCGA- PanCancer Atlas) were explored using the cBioPortal platform. For clarity, only a subset of highly altered and metabolic genes are shown. EGFR, PTEN, TERT, and several metabolic genes such as IDH 1/2, HK2, MYC, LDHA, EZH2 were frequently altered in glioblastoma tumors.

Figure 2

Overview of the major genetic alterations that drive metabolic reprogramming in Gliomas. Metabolic changes observed in gliomas and especially in glioblastoma are associated with several genetic abnormalities, mainly, IDH ½ mutation, EGFR amplification, mutation, or EGFRvIII activation. Also, PTEN loss, and TERT promoter mutation. Various metabolic pathways are affected, yielding a new metabolic profile that supports the high proliferative characteristic, cell adaption, and tumor progression. EZH2, Enhancer of zeste homolog 2; D2HG, d-2-hydroxyglutarate; SREPP 1, sterol regulatory element-binding protein 1; LPCAT1, lysophosphatidylcholine acyltransferase 1; LDLR, glutamate dehydrogenase 1; LDHA, Lactate dehydrogenase A; GDH 1, glutamate dehydrogenase 1; PGK 1, phosphoglycerate kinase 1.

Figure 3

Glycolysis and its role in Glioblastoma cell proliferation and immune escape. The Warburg effect enables GBM cells to meet their energy demand through rapid ATP production, and promotes nucleotides synthesis and oxidative stress management, promoting cell proliferation. The elevated lactate production by tumor cells increases the acidification of the Tumor Microenvironment, which disturbs immune cells activation leading to impaired tumor immunosurveillance and cell migration. Immune cells (tumor-associated macrophages and Microglia) enhance glycolysis through Interleukin-6 (IL-6) and Epidermal Growth Factor (EGF), While hypoxic conditions in the Tumor microenvironment promote glycolysis and Warburg effect by activation and stabilization of hypoxia-inducible transcription factor (HIF-1α).

Figure 4

Schematic illustration of adaptive lipid metabolism in glioblastoma: role of the highly expressed ACBP, DGAT1, GPx4, and lipid droplets in lipid oxidation and ferroptosis induction. FAs, Fatty acids; FAO, Fatty acid oxidation; PUFA, Polyunsaturated fatty acids; DGAT1, diacylglycerol-acyltransferase 1; ACSL4, acyl-CoA synthetase long-chain family member 4; GPX4, glutathione peroxidase; GR, glutathione reductase; LD, lipid Droplet; LPO, lipid peroxides; ACBP, Acyl-CoA-binding protein; LDLR, low-density lipoprotein receptor; ER, Endoplasmic Reticulum.