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Infiltrative and drug‐resistant slow‐cycling cells support metabolic heterogeneity in glioblastoma
Author(s) -
HoangMinh Lan B,
Siebzehnrubl Florian A,
Yang Changlin,
SuzukiHatano Silveli,
Dajac Kyle,
Loche Tyler,
Andrews Nicholas,
Schmoll Massari Michael,
Patel Jaimin,
Amin Krisha,
Vuong Alvin,
JimenezPascual 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,
Deleyrolle Loic P
Publication year - 2018
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.15252/embj.201798772
Subject(s) - biology , cycling , glioblastoma , drug resistance , drug , cancer research , genetics , pharmacology , history , archaeology
Metabolic reprogramming has been described in rapidly growing tumors, which are thought to mostly contain fast‐cycling cells ( FCC s) 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 FCC s harness aerobic glycolysis, and slow‐cycling cells ( SCC s) preferentially utilize mitochondrial oxidative phosphorylation for their functions. SCC s display enhanced invasion and chemoresistance, suggesting their important role in tumor recurrence. SCC s also demonstrate increased lipid contents that are specifically metabolized under glucose‐deprived conditions. Fatty acid transport in SCC s is targetable by pharmacological inhibition or genomic deletion of FABP 7, both of which sensitize SCC s to metabolic stress. Furthermore, FABP 7 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 FABP 7 is central to lipid metabolism in SCC s and that targeting FABP 7‐related metabolic pathways is a viable therapeutic strategy.