Glycomaterials to Investigate the Functional Role of Aberrant Glycosylation in Glioblastoma

Abstract

Glioblastoma (GBM) is a stage IV astrocytoma that carries a dismal survival rate of ≈10 months postdiagnosis and treatment. The highly invasive capacity of GBM and its ability to escape therapeutic challenges are key factors contributing to the poor overall survival rate. While current treatments aim to target the cancer cell itself, they fail to consider the significant role that the GBM tumor microenvironment (TME) plays in promoting tumor progression and therapeutic resistance. The GBM tumor glycocalyx and glycan-rich extracellular matrix (ECM), which are important constituents of the TME have received little attention as therapeutic targets. A wide array of aberrantly modified glycans in the GBM TME mediate tumor growth, invasion, therapeutic resistance, and immunosuppression. Here, an overview of the landscape of aberrant glycan modifications in GBM is provided, and the design and utility of 3D glycomaterials are discussed as a tool to evaluate glycan-mediated GBM progression and therapeutic efficacy. The development of alternative strategies to target glycans in the TME can potentially unveil broader mechanisms of restricting tumor growth and enhancing the efficacy of tumor-targeting therapeutics.

Glycan-Lectin Interactions as Novel Immunosuppression Drivers in Glioblastoma

“…Thus far, an accumulating body of evidences indicate that glycosylation changes occur in GB and involve a large variety of cellular substrates (proteins and lipids) and distinct metabolic pathways, thus contributing to the complex biology and impaired immunogenicity of GB ( Figure 3 ) [ 18 , 74 ].…”

“…On the contrary, α-2,6-sialylation is downregulated in the tumor cells, but it is upregulated in the GB vasculature, suggesting its crucial role for endothelial survival [ 83 , 84 , 85 ]. Therefore, two distinct sialylation pathways underlie distinct biological mechanisms for GB progression [ 74 ]. Little is known about changes in the O -linked mucin type glycosylation.…”

“…Indeed, a glycoproteomic fingerprinting would be of great interest to in depth characterize the ECM components to unveil biological mechanisms aiding cell growth and metastatic spreading that could be useful as potential therapeutic targets [ 74 , 102 ].…”

Identification of glycogene signature as a tool to predict the clinical outcome and immunotherapy response in breast cancer

“…As an important post-translational modification, glycosylation reflects a process in which monosaccharides or entire oligosaccharides (glycans) are enzymatically linked to specific amino acids of proteins (14)(15)(16)(17). Glycosyltransferase, glycosidase, and sulfotransferase related genes are called "glycogenes" that participate in the regulation of glycosylation (18)(19)(20).…”

“…Glycosyltransferase, glycosidase, and sulfotransferase related genes are called "glycogenes" that participate in the regulation of glycosylation (18)(19)(20). Aberrant glycogenes expression or glycosylation actively contributes to tumor progression and is a key hallmark of cancer (14)(15)(16)(17). Clinically, specific glycosylation of glycoprotein expression in blood are defined as tumor biomarkers (CA15-3, CA125 and CA19-9) (21)(22)(23).…”