Metabolic Drivers of Invasion in Glioblastoma

Abstract

Glioblastoma is a primary malignant brain tumor with a median survival under 2 years. The poor prognosis glioblastoma caries is largely due to cellular invasion, which enables escape from resection, and drives inevitable recurrence. While most studies to date have focused on pathways that enhance the invasiveness of tumor cells in the brain microenvironment as the primary driving forces behind GBM's ability to invade adjacent tissues, more recent studies have identified a role for adaptations in cellular metabolism in GBM invasion. Metabolic reprogramming allows invasive cells to generate the energy necessary for colonizing surrounding brain tissue and adapt to new microenvironments with unique nutrient and oxygen availability. Historically, enhanced glycolysis, even in the presence of oxygen (the Warburg effect) has dominated glioblastoma research with respect to tumor metabolism. More recent global profiling experiments, however, have identified roles for lipid, amino acid, and nucleotide metabolism in tumor growth and invasion. A thorough understanding of the metabolic traits that define invasive GBM cells may provide novel therapeutic targets for this devastating disease. In this review, we focus on metabolic alterations that have been characterized in glioblastoma, the dynamic nature of tumor metabolism and how it is shaped by interaction with the brain microenvironment, and how metabolic reprogramming generates vulnerabilities that may be ripe for exploitation.

Keywords: brain tumor; glioblastoma; invasion; metabolism; microenvironment.

FIGURE 1

A schematic representation of metabolic pathways associated with GBM invasion. The proteins highlighted in red are hypothesized to drive invasion in GBM cells. Created using Biorender.com.

FIGURE 2

A schematic representation highlighting the therapeutic interventions associated with GBM metabolism. The red, green, and blue dots depict the interventions using novel targeted inhibitors, dietary interventions, and repurposed drugs, respectively. Created using Biorender.com.