ANGI-01. FGFR1-DRIVEN BRACHYURY PROMOTES ENDOTHELIAL TRANSDIFFERENTIATION OF GLIOBLASTOMA STEM CELLS VIA INTERACTION WITH SOX2/ZEB1/YAP1

Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor. It is characterized by intensive vascular proliferation that is associated with tumor cell growth, invasion, resistance to chemo/radiotherapy, and decreased disease-free survival. Recent data indicate the existence of cells with endothelial characteristics called tumor derived endothelial cells, which come from the transdifferentiation of GBM cells and, more specifically, from GBM stem cells (GSCs). However, the molecular mechanisms underlying this process remain largely unknown. Brachyury is a transcription factor expressed in normal, undifferentiated embryonic notochord in the axial skeleton and plays an important role in stem cell development and vasculogenesis during normal embryonic development. Here, we show that brachyury is highly expressed in patient-derived GBM tissues and cells and is also associated with angiogenic gene expression. Patients with co-expression of brachyury and angiogenesis-related genes have poor survival. Functional studies demonstrate that brachyury activation promotes GSC transdifferentiation into endothelial cells via interaction with SOX2/ZEB1/YAP1. Our studies further show that brachyury-driven endothelial transdifferentiation of GSCs is regulated by FGFR1, and pharmacological inhibition of FGFR1 suppresses brachyury-driven neurosphere and vascular tube formation. In vivo administration of FGFR1 inhibitor or VLP-packaged Cas9/brachyury construct resulted in significant downregulation of brachyury, blocked neovascularization, and reduced tumor growth. These findings highlight the importance of FGFR1-regulated brachyury activation in GSC-derived neovascularization. Targeting the FGFR1-directed brachyury/SOX2/ZEB1/YAP1 signaling pathway may represent a novel strategy for reducing neovascularization in GBM.