The O‑GlcNAcase inhibition by Thiamet G disrupts the AngioMatrix signature of the Glioblastoma secretome in silico and impairs its angiogenic capacity in vitro

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.