McGill University, The Research Institute of the McGill University Health Centre, Montreal, QC, Canada.
Department of Biochemistry, McGill University, Montreal, QC, Canada.
Nat Commun. 2024 Apr 3;15(1):2865. 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.
针对胶质母细胞瘤（GBM）中的新生血管生成的靶向治疗受到对潜在机制的理解不足和与肿瘤分子图谱的关联不明确的阻碍。在这里，我们报告说，不同的人类神经胶质瘤干细胞（GSC）分子亚型触发涉及血管生成或环形血管生长（血管空化）的不同内皮反应。后一种过程是由间充质（而非神经前体细胞）GSC 选择性触发的，由能够将 EGFR/EGFRvIII 转录本转移至内皮细胞的一组特定的细胞外囊泡（EV）介导。在体外，通过药理学（达克替尼）或遗传（基因编辑）抑制内皮细胞中 EGFR 的表达和磷酸化，可消除它们的 EV 反应，并在体内破坏血管空化。在小鼠中，EGFR 的抑制治疗可显著延长抗血管内皮生长因子（VEGF）阻断的抗癌作用，同时消除血管空化并延长生存期。因此，由致癌性 EGFR 的细胞间转移驱动的血管空化可能是 GBM 亚群中的一个新的治疗靶点。
