Blood-brain barrier disruption defines the extracellular metabolome of live human high-grade gliomas
Cécile Riviere-Cazaux, Lucas P. Carlstrom, Karishma Rajani, Amanda Munoz-Casabella, Masum Rahman, Ali Gharibi-Loron, Desmond Brown, Kai J. Miller, Jaclyn J. White, Benjamin Himes, Ignacio Jusué-Torres, Samar Ikram, Seth C. Ransom, Renee Hirte, Ju‐Hee Oh, William F. Elmquist, Jann N. Sarkaria, Rachael A. Vaubel, Moses Rodriguez, Arthur E. Warrington, Sani H. Kizilbash, Terry C. Burns
Abstract
The extracellular microenvironment modulates glioma behaviour. It remains unknown if blood-brain barrier disruption merely reflects or functionally supports glioma aggressiveness. We utilised intra-operative microdialysis to sample the extracellular metabolome of radiographically diverse regions of gliomas and evaluated the global extracellular metabolome via ultra-performance liquid chromatography tandem mass spectrometry. Among 162 named metabolites, guanidinoacetate (GAA) was 126.32x higher in enhancing tumour than in adjacent brain. 48 additional metabolites were 2.05-10.18x more abundant in enhancing tumour than brain. With exception of GAA, and 2-hydroxyglutarate in IDH-mutant gliomas, differences between non-enhancing tumour and brain microdialysate were modest and less consistent. The enhancing, but not the non-enhancing glioma metabolome, was significantly enriched for plasma-associated metabolites largely comprising amino acids and carnitines. Our findings suggest that metabolite diffusion through a disrupted blood-brain barrier may largely define the enhancing extracellular glioma metabolome. Future studies will determine how the altered extracellular metabolome impacts glioma behaviour.