Enhanced fatty acid oxidation provides glioblastoma cells metabolic plasticity to accommodate to its dynamic nutrient microenvironment

Shiva Kant,Ichiro Nakano,Antony Prabhu,Stewart F Graham,Prakash Chinnaiyan,Katie L Buelow,Pravin Kesarwani

doi:10.1038/s41419-020-2449-5

Shiva Kant, Ichiro Nakano + Show 5 more

Open Access

https://doi.org/10.1038/s41419-020-2449-5

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Abstract

Despite advances in molecularly characterizing glioblastoma (GBM), metabolic alterations driving its aggressive phenotype are only beginning to be recognized. Integrative cross-platform analysis coupling global metabolomic and gene expression profiling on patient-derived glioma identified fatty acid β-oxidation (FAO) as a metabolic node in GBM. We determined that the biologic consequence of enhanced FAO is directly dependent upon tumor microenvironment. FAO serves as a metabolic cue to drive proliferation in a β-HB/GPR109A dependent autocrine manner in nutrient favorable conditions, while providing an efficient, alternate source of ATP only in nutrient unfavorable conditions. Rational combinatorial strategies designed to target these dynamic roles FAO plays in gliomagenesis resulted in necroptosis-mediated metabolic synthetic lethality in GBM. In summary, we identified FAO as a dominant metabolic node in GBM that provides metabolic plasticity, allowing these cells to adapt to their dynamic microenvironment. Combinatorial strategies designed to target these diverse roles FAO plays in gliomagenesis offers therapeutic potential in GBM.

Highlights

Introduction The World HealthOrganization classifies glioma intoGrades I–IV based on specific pathologic criteria that influence prognosis and clinical management
We demonstrated considerable metabolic reprogramming associated with gliomagenesis, with aberrant lipid metabolism representing a dominant node in GBM
We demonstrated that methylguanine-DNA methyltransferase (MGMT) promoter methylation and IDH1 mutation, two of the strongest prognostic factors in GBM18,19 were evenly distributed among subtypes (Supplementary Fig. S1)

Summary

Introduction

Introduction The World HealthOrganization classifies glioma intoGrades I–IV based on specific pathologic criteria that influence prognosis and clinical management. Official journal of the Cell Death Differentiation Association. Kant et al Cell Death and Disease (2020)11:253 glioma, we recently performed a comprehensive investigation comparing low grade astrocytoma (LGA) and GBM metabolism using global metabolomic profiling on patient-derived tumors[7]. A number of recent investigations have linked enhanced FAO, which represents a multistep process by which FAs are oxidized and broken down into carbon substrates, with tumorigenesis[8]. A majority of investigations have ascribed energy production as the biological consequence of enhanced FAO in cancer, the diverse roles FAO may play beyond ATP, including cataplerotic reactions that provide substrates for amino acids, nucleotide synthesis, and improved redox potential, are being recognized[8,9,10,11]

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