High mannose content of mesenchymal glioblastoma correlates with hydroxyl proton transfer–weighted (HPTw) MRI as noninvasive biomarker of tumor aggressiveness

Glioblastoma (GBM) contains mesenchymal cancer stem cells that drive tumor aggressiveness and recurrence and exhibit aberrant glycosylation during proneural-to-mesenchymal transition. A comprehensive computational analysis of human GBM transcriptomic datasets revealed an up-regulation of 13 genes involved in glycan mannosylation compared to normal brain, and histopathological staining of a tissue array representing 35 GBM cases revealed elevated mannose levels that correlated with increased expression of the mesenchymal marker CD44. Hydroxyl proton transfer-weighted magnetic resonance imaging (HPTw MRI) detected elevated mannose levels in aggressive human mesenchymal GBM in vitro and in vivo but not in GBM with a less aggressive nonmesenchymal phenotype. To establish causation over correlation, inhibiting expression of the mannose-binding lectins LMAN1/2 that regulate intracellular processing of mannosylated proteins decreased the glioma cell HPTw MRI signal. Our findings indicate that HPTw MRI correlates with high mannose and possibly other saccharide levels in mesenchymal GBM cells, serving as a surrogate imaging biomarker for predicting tumor aggressiveness and recurrence.