In a recent review published in Genes & Diseases, researchers from Jinzhou Medical University, Technische Universität Dresden, and Helmholtz-Zentrum Dresden-Rossendorf elucidate the role of EMT in the initiation, progression, and therapeutic response of GBM.
The authors first review existing studies that report EMT-like processes in these tumors. They then detail how several key signaling pathways, such as the TGF-β, PI3K/Akt, Notch, Wnt, and hypoxia-inducible factor pathways, regulate EMT in GBM. TGF-β serves as a dual regulator that, in advanced stages, utilizes Smad2/3/4 complexes and cross-talk with factors like PSAP and MICAL2 to activate mesenchymal transcription factors, SNAIL and TWIST. Simultaneously, the Wnt/β-catenin cascade promotes invasion via nuclear translocation of β-catenin, while the Notch pathway further enhances stemness and migration by suppressing E-cadherin. These mechanisms are integrated by the PI3K/Akt/GSK-3β axis, indicating that these signaling hubs collectively trigger EMT, enhance cellular invasion and therapeutic resistance, and may serve as critical therapeutic targets for inhibiting GBM progression.
Hypoxia drives GBM malignancy and treatment resistance by stabilizing HIF-1α/2α, driving EMT and metastasis via ZEB1 and Hedgehog/GLI1 signaling. Additionally, the authors review how glioma stem cells (GSCs) promote tumor angiogenesis, enhance tumor invasion, and promote both radio- and chemo-therapy resistance. These cells, which can be identified by a diverse array of markers, including CD133, SSEA-1, Nestin, A2B5, BMI1, and LGR5, drive self-renewal, therapeutic resistance, and high tumorigenic potential. EMT induction is intrinsically linked to this stem-cell phenotype, as transcription factors like ZEB1 and TWIST are essential for GSC initiation and sphere-forming capacity.
Developing EMT-targeted therapies for GBM involves a multifaceted approach. Natural compounds such as calycosin, luteolin, and resveratrol suppress GBM invasion by inhibiting TGF-β/Smad and Wnt/β-catenin signaling, effectively downregulating mesenchymal markers. Therapeutic antibodies targeting the HGF/MET axis (e.g., YYB-101) and the PD-L1/MEK/ERK pathway block immune evasion and mesenchymal shifts. Similarly, small-molecule inhibitors such as crizotinib, bozitinib, and metformin—which target the MET, PI3K/Akt, and STAT3 axes—reverse radiation-induced EMT and stemness. However, the clinical efficacy of these strategies remains limited by poor blood-brain barrier (BBB) penetration, high systemic toxicity, and the inherent plasticity of GBM cells, which utilize compensatory signaling to evade targeted inhibition.
This review thus provides critical insights into how EMT regulates GBM tumorigenesis by detailing its molecular mechanisms, the role of GSCs, and emerging EMT-targeted strategies, emphasizing the need for combination therapies to disrupt progression, overcome resistance, and enhance immune responses.
