Cancer metabolism as a central driving force of glioma pathogenesis

Abstract

The recent identification of distinct genetic and epigenetic features in each glioma entity is leading to a multilayered, integrated diagnostic approach combining histologic features with molecular genetic information. Somatic mutations in isocitrate dehydrogenase (IDH) and receptor tyrosine kinase (RTK) pathways are key oncogenic events in diffuse gliomas, including lower grade (grade II and III) gliomas (LGG) and the highly lethal brain tumor glioblastoma (GBM), respectively, where they reprogram the epigenome, transcriptome, and metabolome to drive tumor growth. However, the mechanisms by which these genetic aberrations are translated into the aggressive nature of gliomas through metabolic reprogramming have just begun to be unraveled. The intricate interactions between the oncogenic signaling and cancer metabolism have also been recently demonstrated. Here, we describe a set of recent discoveries on cancer metabolism driven by IDH mutation and mutations in RTK pathways, highlighting the integration of genetic mutations, metabolic reprogramming, and epigenetic shifts, potentially providing new therapeutic opportunities.

Keywords: Genetic-metabolism interaction; Glioma; IDH; Metabolic reprogramming; Molecular genetics; RTK.

Figure 1. Metabolic reprogramming in IDH-mutated gliomas

Mutations in IDH, identified as an early genetic event in grade II/III LGG and secondary GBM, play an important role in gliomas through its neomorphic activity that converts α-KG to an oncometabolite 2-HG. 2-HG stimulates activity of EGLN prolyl 4-hydroxylases enhancing cellular proliferation through the degradation of HIF, and also inhibits α-KG-dependent dioxygenases including Jumonji C histone lysine demethylases (KDMs) and the ten-eleven translocation (TET) family of 5′-methlycytosine hydroxylases leading to methylator phenotypes including G-CIMP and aberrant histone methylation. Additionally, conversion of α-KG to 2-HG is a NADPH-consuming reduction, decreasing intracellular NADPH levels required for the reduction of oxidative stress that promotes tumorigenesis. mut, mutation; mIDH, mutant form of IDH enzymes; GSH, reduced glutathione; ROS, reactive oxygen species; TERT, telomerase reverse transcriptase; ATRX, alpha thalassemia/mental retardation syndrome X-linked; 1p/19q co-del, chromosomes 1p and 19q co-deletion.

Figure 2. Metabolic reprogramming in GBM with mutations in RTK pathways

Genetic alterations of key components of the growth factor receptor-PI3K-Akt signaling pathway are frequently observed in primary (IDH wild-type) GBM, which eventually activate mTOR signaling. c-Myc, a master regulator of cancer metabolism is transcriptionally and functionally regulated by two distinct mTOR complexes, mTORC1 and mTORC2. This circuit of metabolic shifting causes GBM cell resistance to molecularly targeted therapies by maintaining elevated levels of c-Myc. Interestingly, RTK- and Myc-dependent metabolic reprogramming might be also involved in malignant progression of IDH-mutant gliomas. del, deletion; EGFRvIII, epidermal growth factor receptor variant III; mut, mutation; PI3K, phosphoinositide 3-kinase; PIK3CA, phosphatidylinositol (4,5)-bisphosphate 3-kinase catalytic subunit alpha; PIP2, phosphatidylinositol (4,5)-bisphosphate; PIP3, phosphatidylinositol (3,4,5)-trisphosphate; PTEN, phosphatase and tensin homolog deleted on chromosome 10.

Figure 3. Reciprocal interaction of genetics, metabolism and environment in gliomas

Mutations in the cardinal genes for gliomagenesis including IDH and RTK pathway components are the central force to drive metabolic reprogramming in gliomas. By promoting cancer metabolisms, glioma cells avidly take up extracellular nutrients such as glucose and acetate and metabolize them into intermediary metabolites which in turn tailor the genetic signaling by shifting epigenetics as well as post-translationally modifying oncogenic proteins in the cytosol. Ac, acetyl-group; Me, methyl-group; K, lysine residues.