Targeting fatty acid metabolism in glioblastoma
Jason Miska, Navdeep S. Chandel
Jason Miska, Navdeep S. Chandel
Published January 3, 2023
Citation Information: J Clin Invest. 2023;133(1):e163448. https://doi.org/10.1172/JCI163448.
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Review Series

Targeting fatty acid metabolism in glioblastoma

Abstract

Glioblastoma (GBM) is a primary tumor of the brain defined by its uniform lethality and resistance to conventional therapies. There have been considerable efforts to untangle the metabolic underpinnings of this disease to find novel therapeutic avenues for treatment. An emerging focus in this field is fatty acid (FA) metabolism, which is critical for numerous diverse biological processes involved in GBM pathogenesis. These processes can be classified into four broad fates: anabolism, catabolism, regulation of ferroptosis, and the generation of signaling molecules. Each fate provides a unique perspective by which we can inspect GBM biology and gives us a road map to understanding this complicated field. This Review discusses the basic, translational, and clinical insights into each of these fates to provide a contemporary understanding of FA biology in GBM. It is clear, based on the literature, that there are far more questions than answers in the field of FA metabolism in GBM, and substantial efforts should be made to untangle these complex processes in this intractable disease.

Authors

Jason Miska, Navdeep S. Chandel

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Figure 1

Perturbing FA anabolism in GBM.

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Perturbing FA anabolism in GBM. FA anabolic processes are critical for c...
FA anabolic processes are critical for cellular growth, and blockade of anabolism is mostly associated with inhibition of glioma stem cell phenotypes and sensitization to anti-GBM therapies (anabolism-targeting strategies and their effects are shown in green). A master regulator of lipid biosynthesis in cells is EGFR-mediated SREBP-1 activation, and several studies have demonstrated that perturbation of this axis has strong antitumor properties. At the nexus of anabolism and catabolism is stearoyl-CoA desaturase (SCD), and there have been considerable efforts to inhibit these enzymes in both GBM and other tumors due to the tumor’s dependence on them to control FA desaturation. Blockade of SCD exerts powerful anti-GBM effects both in vitro and in vivo. FA synthesis is governed by both the multifunctional enzyme fatty acid synthase (FASN) and acetyl-CoA carboxylases (ACC1/2) . Targeting these enzymes prevent Glioma stem cell phenotypes and can promote other antitumor therapies. The role of each of these processes in tumors, their spatiotemporal location and activities, and how they promote therapy resistance are under active investigation.