Does Blood-Brain Barrier Disruption Define the Glioma Extracellular Metabolome?

Abstract

Gliomas present a formidable challenge for translational progress. Heterogeneity within and between tumors may demand empirically individualized insights, though relatively little is known about the biochemical milieu within which malignant cells thrive in the in vivo human glioma. We performed a pilot study of intraoperative high molecular weight microdialysis to sample the extracellular tumor environment within three locations in each of five molecularly diverse human gliomas spanning WHO grade 2 oligodendroglioma to WHO grade 4 glioblastoma (GBM). Microdialysates were subjected to targeted (D/L-2-hydroxyglutarate (2-HG)) and untargeted metabolomic analyses, enabling correlation, clustering, fold change, and enrichment analyses. IDH-mutant tumor microdialysate contained markedly higher levels of D2-HG than IDH-wild type tumors. However, IDH status was not predictive of the global metabolomic signature. Rather, two distinct metabolic phenotypes (α and β) emerged, with IDH-WT and IDH-mutant patient samples in each group. Individualized metabolic signatures of enhancing tumor versus adjacent brain were conserved across patients with glioblastoma regardless of metabolic phenotype. Untargeted metabolomic analysis additionally enabled correlative quantification of multiple peri-operatively administered drugs, illustrating regional heterogeneity of blood-brain barrier permeability. As such, acute intraoperative microdialysis affords a previously unharnessed window into individualized heterogeneous microenvironments within and between live human gliomas. Such access to the interstitial milieu of live human gliomas may provide a complementary tool for the development of individualized glioma therapies.

The dynamic impact of location and resection on the glioma CSF proteome

“…Nevertheless, plasma-associated aptamers were strongly enriched in glioma CSF at the time of maximal tumor burden when compared to early post-resection CSF (FDR=0.000; Supplementary Figure 1Di), aligning with our recent findings in the glioma extracellular metabolome wherein blood-brain barrier portions of the tumor were enriched for plasma-derived metabolites (44). This finding suggests that certain proteins in the CSF glioma proteome may be impacted by plasma-derived proteins that cross the tumor-disrupted BBB.…”

“…Our prior findings via microdialysis suggest that the tumor microenvironment is more enriched for plasma-derived metabolites in the BBB disrupted as compared to BBB intact portions of the tumor (44). As such, it is possible that tumor-associated blood-brain barrier disruption may contribute to a portion of the glioma proteome.…”

“…We recently demonstrated that the extracellular glioma metabolome is enriched for plasma-associated metabolites, consistent with relative blood-brain barrier (BBB) disruption in contrast-enhancing regions (44). As resection should decrease the abundance of gliomaassociated proteins, some of which could be due to BBB disruption, we asked whether resection could alter the relative enrichment of the CSF proteome for plasma-derived proteins.…”