Wnt/β-Catenin Signaling in Glioblastoma Biology

The canonical Wnt/β-catenin pathway orchestrates cell fate, proliferation and differentiation in embryonic development and adult tissues. In glioblastoma multiforme, aberrant activation of Wnt signalling drives accumulation of β-catenin in the nucleus, where it binds TCF/LEF transcription factors to up-regulate genes that promote tumour cell survival, invasion and stem-like behaviour. Elevated Wnt activity supports a subpopulation of glioma stem-like cells (GSCs) characterised by self-renewal and resistance to standard therapies. Crosstalk between Wnt/β-catenin and other oncogenic cascades—such as PI3K/Akt, Notch and Hedgehog—further amplifies malignant traits and contributes to immune evasion. In parallel, Wnt-mediated remodelling of the tumour microenvironment enhances angiogenesis and suppresses anti-tumour immunity. Therapeutic modulation of this pathway holds promise, yet early inhibitors have encountered resistance and off-target effects. Emerging strategies focus on novel entry nodes, dual-target approaches and combination treatments with immunotherapies or radiochemotherapy, aiming to overcome tumour heterogeneity and adaptive feedback mechanisms.

Research from Nature Portfolio

Recent studies have elucidated alternative mechanisms of canonical Wnt activation independent of ligand secretion. Semaphorin 3C has been identified as a non-canonical driver that promotes β-catenin nuclear accumulation via Rac1-dependent signalling. This bypass mechanism underlies resistance to upstream Wnt inhibitors, and dual targeting of Sema3C and β-catenin partners such as TCF1 in animal models extended survival beyond single-agent approaches. These findings unveil novel resistance pathways and suggest combination strategies that may achieve sustained suppression of proliferative and stem-like programmes in glioblastoma.

Wnt/β-Catenin Signaling in Glioblastoma Biology publication trend

The graph below shows the total number of articles in wnt/β-catenin signaling in glioblastoma biology across all publications each year (not limited to Nature Index journals).

Technical terms

Wnt/β-catenin signalling: A cellular communication cascade where Wnt ligands stabilise β-catenin, enabling gene transcription that controls proliferation and differentiation.

β-catenin: A central mediator that, upon accumulation in the nucleus, partners with TCF/LEF factors to regulate target gene expression.

Glioma stem-like cells (GSCs): A subpopulation of tumour cells with stem cell properties driving growth, recurrence and treatment resistance.

Tumour microenvironment (TME): The complex network of non-cancerous cells, extracellular matrix and signalling molecules surrounding and influencing tumour growth.

Semaphorin 3C (Sema3C): A neurodevelopmental ligand co-opted in glioblastoma to activate Wnt signalling independently of Wnt ligands.

Chimeric antigen receptor (CAR) T cell: Genetically engineered T cell equipped with synthetic receptors to recognise and kill tumour cells.

References

1. Sema3C signaling is an alternative activator of the canonical WNT pathway in glioblastoma. Nature Communications (2023).
2. TMEM64 aggravates the malignant phenotype of glioma by activating the Wnt/β-catenin signaling pathway. International Journal of Biological Macromolecules (2024).
3. Targeting Wnt signaling for improved glioma immunotherapy. Frontiers in Immunology (2024).
4. Glioma Stem Cells as Promoter of Glioma Progression: A Systematic Review of Molecular Pathways and Targeted Therapies. International Journal of Molecular Sciences (2024).