Epithelial-Mesenchymal Transition Mechanisms in Glioblastoma

Glioblastoma multiforme (GBM) is marked by diffuse infiltration into surrounding brain tissue, rapid recurrence and resistance to conventional therapies. Central to these properties is epithelial-mesenchymal transition (EMT), a phenotypic plasticity programme in which tumour cells downregulate epithelial traits and acquire a motile, mesenchymal phenotype. EMT in GBM involves cadherin switching, cytoskeletal reorganisation and activation of transcription factors such as ZEB1, Snail, Slug and Twist1. These regulators integrate signals from TGF-β, Wnt/β-catenin, PI3K/AKT and hypoxia pathways. Epigenetic mechanisms, including promoter hypermethylation, further stabilise mesenchymal gene expression. EMT fosters invasive behaviour, supports a cancer stem cell state and contributes to chemoresistance, notably via MGMT upregulation and enhanced DNA repair. Recent efforts aim to disrupt EMT regulators or reverse mesenchymal signatures to improve outcomes. Targeting components of the EMT network holds promise for limiting GBM dissemination and overcoming therapeutic resistance.

Research from Nature Portfolio

Recent studies have revealed that downregulation of ephrinB2, through promoter hypermethylation and gene deletion, removes repulsive cues that normally limit cell invasion. Under hypoxic conditions or following anti-angiogenic therapy, HIF-1α induces the EMT repressor ZEB2, which binds the ephrinB2 promoter and further suppresses its expression. Genetic or pharmacological inhibition of ZEB2 restores ephrinB2 levels, reduces tumour cell invasion and counters treatment-induced mesenchymal shifts, underscoring ZEB2 as a therapeutic target to impede both baseline invasiveness and resistance mechanisms triggered by anti-angiogenic regimens.

Epithelial-Mesenchymal Transition Mechanisms in Glioblastoma publication trend

The graph below shows the total number of articles in epithelial-mesenchymal transition mechanisms in glioblastoma across all publications each year (not limited to Nature Index journals).

Technical terms

Epithelial-Mesenchymal Transition (EMT): A cellular programme whereby cells lose epithelial adhesion and polarity, gain mesenchymal traits and enhance motility.

Cadherin Switching: The process in which cells downregulate E-cadherin and upregulate N-cadherin to facilitate detachment and invasion.

Glioma Stem Cells (GSCs): A subpopulation within GBM capable of self-renewal, tumour initiation and resistance to therapies.

Transcription Factor: A protein that binds DNA to regulate gene expression; key EMT regulators include ZEB1, Snail, Slug and Twist1.

Hypoxia-Inducible Factor (HIF): A transcriptional regulator activated under low oxygen tension that drives adaptive and invasive responses.

Mesenchymal Signature: A coordinated expression profile of genes characteristic of the mesenchymal phenotype, often linked to poor prognosis.

References

1. LGR5, a novel functional glioma stem cell marker, promotes EMT by activating the Wnt/β-catenin pathway and predicts poor survival of glioma patients. Journal of Experimental & Clinical Cancer Research (2018).
2. The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance. EMBO Molecular Medicine (2013).
3. Genomics and Prognosis Analysis of Epithelial-Mesenchymal Transition in Glioma. Frontiers in Oncology (2020).
4. EphrinB2 repression through ZEB2 mediates tumour invasion and anti-angiogenic resistance. Nature Communications (2016).