Vascular proximity gives rise to metabolic zonation in the glioblastoma tumor microenvironment.

  • Major Finding: Vascular proximity gives rise to metabolic zonation in the glioblastoma tumor microenvironment.

  • Concept: mTOR activation in perivascular cancer cells drives enhanced tumorigenicity and chemoresistance.

  • Impact: Metabolic zonation contributes to phenotypic and functional heterogeneity in glioblastoma.

Tumor neovascularization can create perfusion gradients of nutrients and other paracrine factors, suggesting that differences in exposure to vascular signals may result in distinct metabolic niches and functional heterogeneity within tumors. Kumar and colleagues adapted a differential cell labeling technique to sort viable glioblastoma cells by relative distance from blood vessels following intravenous injection of fluorescent dye in mouse xenograft models. This approach allowed for the separation of normoxic tumor cells residing within a few cell layers of perfused vessels and permitted fractionation of these cells based on the level of dye uptake into three subpopulations, which were subjected to high-throughput transcriptomic and metabolomic profiling. Distance from blood vessels correlated with graded differences in overall gene-expression profiles and metabolite content, and perivascular cancer cells with high dye uptake were characterized by enhanced rates of protein and nucleotide synthesis and elevated energy production. In addition, genes related to oxidative phosphorylation were enriched in perivascular cancer cells, which exhibited increased mitochondrial content and activity, consistent with enhanced dependence on mitochondrial respiration. mTOR activation was spatially restricted to perivascular cancer cells in both mouse xenografts and human glioblastoma tumors, and functional assessment revealed that mTOR activation in perivascular cells promoted increased migration and invasiveness, as well as enhanced chemoresistance and radioresistance. This more aggressive phenotype of perivascular glioblastoma cells was a consequence of their mTOR-driven metabolic state, as mTOR inhibition resulted in impaired migratory ability and increased therapeutic sensitivity. Collectively, this work uncovers a privileged metabolic zone in glioblastoma tumors that arises from differential vascular perfusion and reveals that graded metabolic zonation contributes to intratumoral functional heterogeneity.

Kumar S, Sharife H, Kreisel T, Mogilevsky M, Bar-Lev L, Grunewald M, et al. Intra-tumoral metabolic zonation and resultant phenotypic diversification are dictated by blood vessel proximity. Cell Metab 2019 May 2 [Epub ahead of print].

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