Methodological Approaches for Assessing Metabolomic Changes in Glioblastomas

Abstract

Glioblastoma (GBM), a highly malignant primary brain tumor, inevitably leads to death. In the last decade, a variety of novel molecular characteristics of GBMs were unraveled. The identification of the mutation in the IDH1 and less commonly IDH2 gene was surprising and ever since has nurtured research in the field of GBM metabolism. While initially thought that mutated IDH1 were to act as a loss of function mutation it became clear that it conferred the production of an oncometabolite that in turn substantially reprograms GBM metabolism. While mutated IDH1 represents truly the tip of the iceberg, there are numerous other related observations in GBM that are of significant interest to the field, including the notion that oxidative metabolism appears to play a more critical role than believed earlier. Metabolic zoning is another important hallmark of GBM since it was found that the infiltrative margin that drives GBM progression reveals enrichment of fatty acid derivatives. Consistently, fatty acid metabolism appears to be a novel therapeutic target for GBM. How metabolism in GBM intersects is another pivotal issue that appears to be important for its progression and response and resistance to therapies. In this review, we will summarize some of the most relevant findings related to GBM metabolism and cell death and how these observations are influencing the field. We will provide current approaches that are applied in the field to measure metabolomic changes in GBM models, including the detection of unlabeled and labeled metabolites as well as extracellular flux analysis.

Keywords: Cell death; Glioblastoma; IDH1; Metabolic reprogramming; Metabolism.