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.

High Expression of Glycolytic Genes in Clinical Glioblastoma Patients Correlates With Lower Survival

“…A salient feature of GBM cells is that they adjust their metabolic profile to fulfill the bioenergetics and anabolic demands of the high rates of proliferation (Zhou and Wahl, 2019;Garcia et al, 2021). Yet, little is known about the metabolic changes at stages of the disease.…”

“…This may therefore encourage mechanistic exploration of metabolic genes in glycolysis, PPP, TCA cycle and OXPHOS induced changes in tumor aggressiveness and invasiveness contributing to patient survival outcomes. To this end, recent global profiling experiments have identified roles for lipid, amino acid, and nucleotide metabolism in tumor growth and invasion (Prabhu et al, 2019;Garcia et al, 2021). A thorough understanding of the metabolic traits that define invasive GBM cells may lead to novel therapeutic targets for this devastating disease.…”

“…Akin to many other cancers, GBM cells exhibit the Warburg effect, where even in the presence of high levels of oxygen, cancer cells exhibit a strong preference for glycolysis (Cairns et al, 2011;Koppenol et al, 2011). In GBM, glycolysis has been suggested to correlate with tumor proliferation, invasion, angiogenesis, and chemotherapy/radiotherapy resistance (Kathagen-Buhmann et al, 2016;Son et al, 2020;Garcia et al, 2021). In addition, glycolysis could shape the tumor microenvironment (TME) and regulate immune and inflammatory responses (Kesarwani et al, 2019).…”

Lactate saturation limits bicarbonate detection in hyperpolarized 13C‐pyruvate MRI of the brain

“…Acute disturbances in neuro-energetic function are a hallmark of stroke or traumatic injury, 2 while chronic disturbances are important contributors to degenerative, cancerous, and inflammatory diseases. [3][4][5] One key site of metabolic imbalance is at the intersection of glycolysis and glucose oxidation, where pyruvate is metabolized to either acetyl-CoA or lactate. New diagnostic tools capable of detecting imbalances in carbohydrate metabolism at this intersection would provide valuable information for clinicians and researchers alike.…”

Targeted inhibition of ubiquitin signaling reverses metabolic reprogramming and suppresses glioblastoma growth

“…Most cancers, including GBM, have a unique metabolic profile mostly based on aerobic glycolysis, also known as the Warburg effect 41 , 42 . The glycolytic profile of cancer cells is inhibited by AMPK that, once activated, suppresses glycolysis and inhibits tumor growth 43 .…”