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Hsu, Wesley; Zehri, Aqib; Hu, Yunping
Neuro-oncology, 11/2022, Letnik: 24, Številka: Supplement_7Journal Article
Abstract Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median survival of only 15 months and a 5-year survival of less than 5% despite the best available treatments. Tumor recurrence/progression and therapy resistance are major obstacles for GBM treatment. GBM is characterized by intensive vascular proliferation that is associated with tumor cell growth, invasion, resistance to chemo/radiotherapy, and decreased disease-free survival. Increasing data have shown 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. GSCs are tightly regulated by distinct transcriptional programs that are driven by nuclear transcription factors. 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 differentiation during normal embryonic development. Here, we show that brachyury is highly expressed in patient-derived GBM cells. Functional studies demonstrate that brachyury is regulated by fibroblast growth factor receptor 1 (FGFR1)/mitogen-activated protein kinase (MAPK). Our studies further disclose that FGFR1/MAPK-directed brachyury activation promotes GSC survival and endothelial formation via vascular endothelial growth factor receptor 2 (VEGFR2), whereas pharmacological inhibition of FGFR1 and MAPK or shRNA-mediated downregulation of brachyury decreases GSC transdifferentiation into endothelial cells and suppresses GBM cell growth and stemness via VEGFR2. Our findings highlight the importance of FGFR1/MAPK-regulated brachyury activation in GSC transdifferentiation into endothelial cells via VEGFR2, and targeting the FGFR1-MAPK-brachyury-VEGFR2 signal pathway may represent a novel therapeutic strategy by reprogramming GSCs driving vascular transdifferentiation and tumor progression.
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