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

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.

ADAMDEC1 maintains a novel growth factor signaling loop in cancer stem cells

“…The relevance of FGFR1 for GSCs is further supported by increased survival after loss of FGFR1, as well as increased tumorigenicity of FGFR1+ cells. We and others have shown that ZEB1 is a key regulator of stemness, invasion and chemoresistance in GBM (7,12,42), and consistently we find that ZEB1 mediates the stemness effects of FGF2/FGFR1 signaling. Singh and colleagues have recently demonstrated that ZEB1, SOX2 and OLIG2 form an autonomous transcriptional loop in GBM, and can regulate their expression reciprocally (26).…”

“…Human glioblastoma (hGBM) cells were cultured as described previously (7,12). Briefly, for GSC sphere culture, 5x10 4 Cell lines from the HGCC repository (28) were cultured in Neurobasal medium (Thermo Fisher) supplemented with B27 (Thermo Fisher) and 20ng/ml EGF and FGF2.…”

“…Immunostaining and flow cytometry was performed as described (12). Data was acquired on a BD LSR Fortessa (BD Bioscience), using FACSDIVA software (BD Bioscience) and…”

“…Frequent tumor recurrence and poor outcome are thought to be a consequence of resident GBM cancer stem cell (GSC) populations resistant to current therapies (6)(7)(8). Thus, GSCs are a candidate population for tumor recurrence (9)(10)(11)(12). A recent study demonstrated that GBM contains GSC populations that produced non-stem cancer cell (NSCC) progenies, with only GSCs capable of propagating tumor formation (13).…”

Neural G0: a quiescent-like state found in neuroepithelial-derived cells and glioma

“…PTN and its target PTPRZ1 also may help promote stemness, signaling, and proliferation of neural progenitors and glioma tumor cells (Fujikawa et al 2016;Zhang et al 2016;Fujikawa et al 2017). Moreover, FABP7 expression and activity have been associated with lipid metabolism in slow-cycling GBM tumor cells, proposed to be responsible for tumor recurrence (Hoang-Minh et al 2018).…”