Detection of Aggressive Mesenchymal Glioblastoma by Mannose-Weighted CEST MRI

Glioblastoma (GBM) contain mesenchymal cancer stem cells that drive tumor aggressiveness and recurrence and exhibit aberrant glycosylation during proneural-to-mesenchymal transition. A comprehensive analysis of human GBM transcriptomic datasets revealed an upregulation of 13 genes involved in mannosylation. Histopathological staining of a tissue array representing 35 GBM cases revealed elevated mannose, correlating with increased expression of the mesenchymal marker CD44. Mannose-weighted chemical exchange saturation transfer magnetic resonance imaging (MANw CEST MRI) detected elevated mannose levels in aggressive mesenchymal GBM neurospheresin vitroandin vivo, but not in less aggressive non-mesenchymal phenotype. To establish causation, inhibiting the expression of the mannose binding lectins LMAN1/2 that regulate intracellular processing of mannosylated proteins decreased the glioma cell MANw CEST MRI signal. Our findings indicate that MANw CEST MRI can visualize high mannose levels in mesenchymal GBM cells, which may serve as a surrogate imaging biomarker for predicting and assessing tumor aggressiveness and recurrence.