Glycosylation-dependent lectin-receptor interactions preserve angiogenesis in anti-VEGF refractory tumors

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Clinical benefit of vascular endothelial growth factors (VEGF)-targeted therapies is often limited by tumor resistance.
• Tumor regrowth after anti-VEGF treatment suggests compensatory mechanisms for angiogenesis.

Purpose of the Study:

• To identify glycosylation-dependent pathways that promote angiogenesis and tumor resistance to VEGF blockade.
• To explore targeting lectin-receptor interactions for enhancing anti-VEGF therapy efficacy.

Main Methods:

• Analyzed endothelial cell (EC) surface glycome remodeling in response to VEGF blockade.
• Investigated the role of galectin-1 (Gal1) binding to VEGFR2 via N-glycans.
• Assessed the impact of altering glycosylation patterns (e.g., sialic acid, β1-6GlcNAc branching) and Gal1 levels on tumor response to anti-VEGF therapy.

Main Results:

• Tumor resistance to anti-VEGF therapy is mediated by a pathway involving EC surface glycome remodeling and galectin-1 (Gal1) binding to VEGFR2.
• Anti-VEGF-sensitive tumors have high α2-6-linked sialic acid, preventing Gal1 binding, while refractory tumors show increased Gal1 and permissive glycosylation.
• Interfering with Gal1-N-glycan interactions or reducing Gal1 levels converted refractory tumors to an anti-VEGF-sensitive state.
• Disrupting the Gal1-N-glycan axis promoted vascular remodeling, immune cell infiltration, and inhibited tumor growth.

Conclusions:

• Glycosylation-dependent galectin-1 (Gal1) interactions with VEGFR2 represent a key mechanism for tumor resistance to anti-VEGF therapy.
• Targeting the Gal1-N-glycan axis offers a promising strategy to overcome resistance and improve the efficacy of anti-VEGF treatments.