Glioblastoma (GBM), a malignant tumor originating from glial, is the most common primary tumor of the central nervous system and the most aggressive form of glioma. Despite surgery, radiation, and chemotherapy, recurrence is almost inevitable, and the five-year survival rate remains around 25%. A major reason for this resilience is the ability of GBM cells to adapt and resist therapy. Epithelial‒mesenchymal transition (EMT), a process in which epithelial cells undergo transformation into cells with a mesenchymal phenotype, has emerged as a central mechanism underlying this adaptability.

A recent review published in Genes & Diseases from Jinzhou Medical University, Technische Universität Dresden and Helmholtz-Zentrum Dresden-Rossendorf, summarizes the roles of EMT in GBM initiation and progression, its impact on cancer cell behavior, and the challenges of targeting EMT in therapy, highlighting potential strategies to overcome resistance and improve treatment outcomes.

The review explains how EMT in GBM is driven by a complex network of signaling pathways, including TGF-β, PI3K/Akt, Wnt/β-catenin, Notch, and hypoxia-inducible factors. Activation of these pathways not only promotes tumor cell migration and invasion but also maintains a population of glioblastoma stem cells (GSCs) that are resistant to chemotherapy and radiation.
Importantly, the review identifies several molecular markers, such as N-cadherin, vimentin, and EMT-inducing transcription factors like TWIST, SNAIL, and ZEB, that correlate with poor prognosis. High expression of these genes predicts shorter overall survival, underscoring their potential as biomarkers for patient stratification and disease monitoring.

The review also highlights emerging therapeutic strategies to disrupt EMT and its downstream effects. Natural compounds such as resveratrol, luteolin, and melatonin have shown the ability to interfere with EMT signaling. Monoclonal antibodies like YYB-101 and small-molecule inhibitors, including metformin, foretinib, and STAT3 inhibitors, also demonstrate potential. These approaches aim to reduce tumor invasion, enhance sensitivity to standard therapies, and limit recurrence.

However, the review cautions that GBM’s remarkable cellular plasticity and the protective blood–brain barrier (BBB) remain major challenges. Tumor cells can activate compensatory signaling routes when one pathway is inhibited, limiting the durability of EMT-targeted treatments. The review emphasizes the need for agents that can cross the BBB, combination treatments that tackle multiple pathways, and biomarker-based patient selection to personalize therapy.

By mapping the intricate interplay between EMT, glioblastoma stemness, and treatment resistance, this review provides a strong foundation for future research. It encourages the development of next-generation inhibitors, nanotechnology-based drug delivery systems, and strategies that combine EMT-targeting drugs with existing treatments.

Reference

Title of Original Paper: The significance of epithelial‒mesenchymal transition (EMT) in the initiation, plasticity, and treatment of glioblastoma

Journal: Genes & Diseases

Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI: https://doi.org/10.1016/j.gendis.2025.101711

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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus Cite Score: 8.4 | Impact Factor: 9.4

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