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Infiltrative and drug-resistant slow-cycling cells support metabolic heterogeneity in glioblastoma

Hoang-Minh, Lan B, Siebzehnrubl, Florian, Yang, Changlin, Suzuki-Hatano, Silveli, Dajac, Kyle, Loche, Tyler, Andrews, Nicholas, Schmoll Massari, Michael, Patel, Jaimin, Amin, Krisha, Vuong, Alvin, Jimenez Pascual, Ana, Kubilis, Paul, Garrett, Timothy J, Moneypenny, Craig, Pacak, Christina A, Huang, Jianping, Sayour, Elias J, Mitchell, Duane A, Sarkisian, Matthew R, Reynolds, Brent A and Deleyrolle, Loic P 2018. Infiltrative and drug-resistant slow-cycling cells support metabolic heterogeneity in glioblastoma. EMBO Journal 37 (22) , e98772. 10.15252/embj.201798772

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Abstract

Metabolic reprogramming has been described in rapidly growing tumors, which are thought to mostly contain fast‐cycling cells (FCCs) that have impaired mitochondrial function and rely on aerobic glycolysis. Here, we characterize the metabolic landscape of glioblastoma (GBM) and explore metabolic specificities as targetable vulnerabilities. Our studies highlight the metabolic heterogeneity in GBM, in which FCCs harness aerobic glycolysis, and slow‐cycling cells (SCCs) preferentially utilize mitochondrial oxidative phosphorylation for their functions. SCCs display enhanced invasion and chemoresistance, suggesting their important role in tumor recurrence. SCCs also demonstrate increased lipid contents that are specifically metabolized under glucose‐deprived conditions. Fatty acid transport in SCCs is targetable by pharmacological inhibition or genomic deletion of FABP7, both of which sensitize SCCs to metabolic stress. Furthermore, FABP7 inhibition, whether alone or in combination with glycolysis inhibition, leads to overall increased survival. Our studies reveal the existence of GBM cell subpopulations with distinct metabolic requirements and suggest that FABP7 is central to lipid metabolism in SCCs and that targeting FABP7‐related metabolic pathways is a viable therapeutic strategy.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Biosciences
European Cancer Stem Cell Research Institute (ECSCRI)
Publisher: EMBO Press
ISSN: 0261-4189
Date of First Compliant Deposit: 18 October 2018
Date of Acceptance: 24 August 2018
Last Modified: 17 Oct 2019 21:23
URI: http://orca-mwe.cf.ac.uk/id/eprint/115991

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