Distinct spatial N-glycan profiles reveal glioblastoma-specific signatures.

in The Journal of pathology by Aaron O Angerstein, Lyndsay E A Young, Thatchawan Thanasupawat, Jerry Vriend, Grace Grimsley, Xueqing Lun, Donna L Senger, Namita Sinha, Jason Beiko, Marshall Pitz, Sabine Hombach-Klonisch, Richard R Drake, Thomas Klonisch

TLDR

  • This study examined the complex relationships between glycosylation patterns and tumour biology in human malignant glioma, identifying potential N-glycan markers for TMZ treatment response and resistance.

Abstract

This study explored the complex interactions between glycosylation patterns, tumour biology, and therapeutic responses to temozolomide (TMZ) in human malignant glioma, specifically CNS WHO grade 3 oligodendroglioma (ODG) and glioblastoma (GB). Using spatial imaging of N-glycans in formalin-fixed paraffin-embedded (FFPE) tissue sections via MALDI-MSI, we analysed the N-glycome in primary and recurrent GB tissues and orthotopic xenografts of patient-derived brain tumour-initiating cells (BTIC) sensitive or resistant to TMZ. We identified unique N-glycosylation profiles, with nontumor brain (NTB) and ODG showing higher levels of bisecting and tri-antennary structures, while GB exhibited more tetra-antennary and sialylated N-glycans. Distinctive sialylation patterns were observed, with specific α2,6 and α2,3 isomeric linkages significantly altered in GB. Moreover, comparative analysis of primary and recurrent GB tissues revealed elevated high mannose N-glycans in primary GB and fucosylated bi- and tri-antennary N-glycans in recurrent GB tissues. Next, in the orthotopic xenografts of TMZ-sensitive and TMZ-resistant patient brain tumour initiating cells (BTIC), we identified potential N-glycan markers for TMZ treatment response and resistance. Finally, we found significantly altered expression of genes involved in N-glycan biosynthesis in malignant glioma, highlighting the crucial role of N-glycans in glioma and therapy resistance. This study lays the foundation for developing glycosylation-based diagnostic biomarkers and targeted therapies, potentially improving clinical outcomes for GB patients. © 2025 The Pathological Society of Great Britain and Ireland.

Overview

  • The study investigated the intersections between glycosylation patterns, tumour biology, and therapeutic responses to temozolomide (TMZ) in human malignant glioma, focusing on CNS WHO grade 3 oligodendroglioma (ODG) and glioblastoma (GB).
  • The research employed spatial imaging of N-glycans in formalin-fixed paraffin-embedded (FFPE) tissue sections via MALDI-MSI to analyze the N-glycome in primary and recurrent GB tissues, as well as orthotopic xenografts of patient-derived brain tumour-initiating cells (BTIC) sensitive or resistant to TMZ.
  • The primary objective was to identify potential N-glycan markers for TMZ treatment response and resistance, and to explore the role of N-glycans in glioma and therapy resistance.

Comparative Analysis & Findings

  • The study revealed unique N-glycosylation profiles, with nontumor brain (NTB) and ODG showing higher levels of bisecting and tri-antennary structures, while GB exhibited more tetra-antennary and sialylated N-glycans.
  • Distinctive sialylation patterns were observed, with specific α2,6 and α2,3 isomeric linkages significantly altered in GB.
  • Comparative analysis of primary and recurrent GB tissues revealed elevated high mannose N-glycans in primary GB and fucosylated bi- and tri-antennary N-glycans in recurrent GB tissues.

Implications and Future Directions

  • The study highlights the crucial role of N-glycans in glioma and therapy resistance, suggesting a potential link between altered glycosylation patterns and treatment outcomes.
  • The identification of N-glycan markers for TMZ treatment response and resistance suggests the possibility of developing glycosylation-based diagnostic biomarkers and targeted therapies.
  • Further research is needed to explore the role of N-glycans in glioma development and progression, as well as to investigate the potential therapeutic applications of glycosylation-based interventions.
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