Targeting MGAT4A‐Mediated N‐Glycosylation as a Therapeutic Strategy to Inhibit Glioblastoma Stem Cell Invasion
Year: 2026
Type: article
Abstract: Glioblastoma (GBM) is the most aggressive type of primary brain tumor, and its invasive properties contribute significantly to incomplete surgical resection and tumor recurrence. Despite extensive clinical efforts to mitigate GBM invasion, targeted therapies against GBM stem cells (GSCs), which drive invasion, remain incompletely understood. Here, we report that MGAT4A, a key glycosyltransferase involved in N-glycosylation, orchestrates EGFR-ERK1/2 signaling to promote GSC invasion. Elevated MGAT4A expression correlates with poor survival outcomes in GBM patients, highlighting its potential as a therapeutic target. Silencing MGAT4A inhibits GSC invasion and tumorigenic capacities, including self-renewal and proliferation, both in vitro and in an orthotopic brain tumor xenograft model. Proteomic N-glycosylation mapping and co-immunoprecipitation assays reveal that MGAT4A interacts with EGFR and catalyzes N-glycosylation at the EGFR N604 site. This modification triggers ERK1/2 phosphorylation, thereby driving the invasion and tumorigenic potential of GSCs. Notably, tunicamycin, an N-glycosylation inhibitor, significantly impedes GSC invasion and disrupts downstream EGFR-ERK1/2 signaling, extending survival in mice bearing orthotopic tumors. To specifically target MGAT4A, we developed a CRISPR-Cas9 sgRNA-based nanotechnology, which notably reduced GSC invasion and improved survival in mice. Collectively, our study elucidates a novel mechanistic pathway driving GSC invasion and positions MGAT4A as a promising therapeutic target for GBM.
Source: Exploration
DOI: 10.1002/exp.20250153
Authors: Rui Niu, Meichen Liu, Qingshan Yang, Jinlong Yin
Institutions: Henan University, National Cancer Center
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $3,500
Award: G6689797592
OpenAlex ID: W7124439349