Mesenchymal glioma stem cells trigger vasectasia—distinct neovascularization process stimulated by extracellular vesicles carrying EGFR

• Published in: Nature communications 2024-04, Vol.15 (1), p.2865-2865, Article 2865
• Main Authors: Spinelli, Cristiana, Adnani, Lata, Meehan, Brian, Montermini, Laura, Huang, Sidong, Kim, Minjun, Nishimura, Tamiko, Croul, Sidney E., Nakano, Ichiro, Riazalhosseini, Yasser, Rak, Janusz
• Format: Article
• Language: English
• Subjects: 13; 14; 14/19; 14/34; 38; 38/91; 59; 59/5; 631/532/71; 631/67/1922; 631/67/395; 631/80/304; 692/4028/67/2328; 96; 96/1; Angiogenesis; Anticancer properties; Blood vessels; Endothelial cells; Epidermal growth factor receptors; Extracellular vesicles; Genetic modification; Genome editing; Glioblastoma; Glioblastoma cells; Glioma; Glioma cells; Humanities and Social Sciences; multidisciplinary; Phosphorylation; Science; Science (multidisciplinary); Stem cells; Therapeutic targets; Vascular endothelial growth factor; Vascularization; Vesicles
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-46597-x

Targeting neovascularization in glioblastoma (GBM) is hampered by poor understanding of the underlying mechanisms and unclear linkages to tumour molecular landscapes. Here we report that different molecular subtypes of human glioma stem cells (GSC) trigger distinct endothelial responses involving either angiogenic or circumferential vascular growth (vasectasia). The latter process is selectively triggered by mesenchymal (but not proneural) GSCs and is mediated by a subset of extracellular vesicles (EVs) able to transfer EGFR/EGFRvIII transcript to endothelial cells. Inhibition of the expression and phosphorylation of EGFR in endothelial cells, either pharmacologically (Dacomitinib) or genetically (gene editing), abolishes their EV responses in vitro and disrupts vasectasia in vivo. Therapeutic inhibition of EGFR markedly extends anticancer effects of VEGF blockade in mice, coupled with abrogation of vasectasia and prolonged survival. Thus, vasectasia driven by intercellular transfer of oncogenic EGFR may represent a new therapeutic target in a subset of GBMs. Vasectasia is a newly described, non-angiogenic form of blood vessel formation induced by mesenchymal glioblastoma cells, and driven by endothelial cell responses to extracellular vesicles containing oncogenic EGFR.