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Published on: March 20, 2026
The O‑GlcNAcase Inhibition by Thiamet G Disrupts the AngioMatrix Signature of the Glioblastoma Secretome In Silico
Marcella Abranches Gil de Castro1, Taina Queiroz1, Aline Cristina de Menezes2
1Pós-graduação em Medicina (Anatomia Patológica), Pós-graduação em Ciências Morfológicas, Universidade Federal do Rio de Janeiro, Brazil.
Abstract:
Glioblastoma (GBM) is the most aggressive tumor in the Central Nervous System for which the standard-of-care treatment is still limited to maximal surgical resection followed by chemotherapy and radiotherapy. Thus, innovative strategies have been investigated to improve GBM treatment and increase patient overall survival. In this work we investigated a putative role for Thiamet G (TMG), an O‑GlcNAcase (OGA) inhibitor, in modulating the angiogenic capacity of GBM secretome using label-free mass spectrometry followed by in vitro validations. In silico analysis showed that TMG treatment of U87-MG GBM cells led to an enrichment of Extracellular Matrix (ECM)-related pathways associated with angiogenic biological processes, or the AngioMatrix, in the GBM secretome coupled to significant fold change of Thrombospondin-2 (THBS2), C-C motif chemokine 2 (CCL2) and Interleukin-6 (IL-6). Among them, only THBS2 gene alteration and CCL2 gene expression were significantly related to overall survival in GBM patients. Further in vitro validation exposing endothelial cells to TMG-treated GBM secretome showed aberrant tubulogenesis and migration, indicating that TMG treatment of GBM cells functionally disrupted the tumor cell capacity of modulating angiogenesis-related processes in vitro. These pioneering results demonstrate the impact of TMG on the AngioMatrix signature of the GBM secretome bridging pharmacological inhibition of OGA activity with innovative approaches targeting anti-angiogenic therapy for GBM treatment.
Insights
Thiamet G (TMG) alters the Glioblastoma (GBM) secretome, disrupting angiogenesis. This O-GlcNAcase inhibitor impacts tumor cell communication, offering potential for novel anti-angiogenic therapies against GBM.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Biochemistry
Background:
- Glioblastoma (GBM) is an aggressive brain tumor with limited treatment options.
- Current standard-of-care involves surgery, chemotherapy, and radiotherapy, with modest survival benefits.
- Innovative strategies targeting tumor biology are crucial for improving GBM patient outcomes.
Purpose of the Study:
- To investigate the effect of Thiamet G (TMG), an O-GlcNAcase (OGA) inhibitor, on the angiogenic secretome of Glioblastoma (GBM) cells.
- To explore the potential of TMG as an anti-angiogenic therapeutic strategy for GBM.
- To identify key proteins in the GBM secretome modulated by TMG treatment.
Main Methods:
- Label-free mass spectrometry was employed to analyze the GBM secretome.
- In silico analysis identified enriched pathways related to angiogenesis (AngioMatrix).
- In vitro assays validated the functional impact of TMG-treated GBM secretome on endothelial cell behavior.
Main Results:
- TMG treatment of U87-MG GBM cells altered the secretome, enriching Extracellular Matrix (ECM)-related pathways linked to angiogenesis.
- Significant changes were observed in Thrombospondin-2 (THBS2), C-C motif chemokine 2 (CCL2), and Interleukin-6 (IL-6) levels.
- TMG-treated GBM secretome impaired endothelial cell tubulogenesis and migration in vitro, indicating disrupted angiogenic signaling.
Conclusions:
- TMG significantly impacts the AngioMatrix signature of the GBM secretome.
- TMG treatment functionally disrupts the GBM cells' ability to modulate angiogenesis-related processes.
- These findings suggest TMG as a promising agent for developing novel anti-angiogenic therapies for Glioblastoma.
