Targeting Wnt/β-Catenin Signaling Shows Promise Against Glioblastoma

Glioblastoma (GBM) is an aggressive form of brain tumor with a poor prognosis. Despite advances in neurosurgery, chemotherapy, and radiotherapy, it remains treatment-resistant and inevitably recurs. The molecular mechanisms underlying glioma development and progression are still poorly understood, and there is an urgent need for more effective therapeutic approaches.

In a recent study published in Genes & Diseases, researchers from Virginia Commonwealth University and The University of Texas MD Anderson Cancer Center, evaluated the efficacy of Wnt-C59 in suppressing GBM growth and progression.

Initially, the research team analysed data from GTEx cortex and TCGA-GBM databases and found that several Wnt proteins and Wnt target genes exhibited increased expression in GBM as compared with the normal cerebral cortex. Similarly, the analysis also revealed that porcupine (PORCN), a critical modulator of Wnt signalling, was also up-regulated in GBM tissues, which correlated with poorer patient survival. In addition, the team found that lipoprotein receptor-related protein 6 (LPR6) was highly phosphorylated (p-LPR6) in the majority of GBM cells, indicating both PORCN and p-LPR6 as major drivers of Wnt hyperactivation in GBM.

Treatment with Wnt-C59, a PORCN inhibitor, reduced β-catenin levels, inhibited Wnt signaling, hindered GBM cell proliferation and invasion, and inhibited GBM stem cells' self-renewal properties in a dose-dependent manner. Additionally, Wnt-C59 also downregulated FOXM1, a downstream transcription target of Wnt/β-catenin signalling, along with Wnt downstream targets genes, cyclin D and c-Myc. Furthermore, Wnt-C59 demonstrated the ability to impede tumor formation and enhance the overall survival of mice bearing GBM in a preclinical model.

Interestingly, the effect of Wnt-C59 monotherapy was significantly augmented when combined with temozolomide (TMZ). This finding supports the potential clinical implementation of this targeted combination therapy for treating GBM. Notably, molecular analyses revealed that Wnt-C59 treatment decreased the expression of oncogenic drivers (Cyclin D1, c-Myc, Rad51) and stemness markers (Nestin, Sox2), providing a clear mechanistic basis for its anti-tumor efficacy.

In conclusion, this study demonstrates that targeting Wnt/β-catenin signaling via PORCN inhibition, especially in combination with TMZ, offers a promising therapeutic strategy for treating GBM. These findings pave the way for the potential development of combinatorial targeted therapies in GBM.

Reference

Title of Original Paper: Targeting Wnt/β-catenin activation in combination with temozolomide leads to glioblastoma inhibition and long-term survival in mice

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.2025.101624

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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.

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(A) The heatmap showing the differential expression of the Wnt proteins and the Wnt target genes between the GTEx cortex (n = 199) and TCGA-GBM (n = 173) datasets. (B) The spatial transcriptomic data showed the expression distribution of Wnt target genes in GBM tissues. The samples include GBM1 and GBM2 (UKF269_T and UKF334_T; Vidhya, 2022), and GBM3 (Patient 4; Yan, 2023). (C, D) The violin plot displaying the GSVA scores of Wnt target genes across RNA sequencing data from GTEx brain, TCGA_LGG, and TCGA-GBM datasets. ***P < 0.001. (E) Analyses of TCGA, CGGA, and Rembrandt datasets revealed that GSVA scores of Wnt target genes inversely correlated with glioma patient survival. The Wnt_target high- and low-expression groups were stratified based on the median GSVA score within each dataset.
(A, B) GSC11 (A) and U87MG (B) cells were treated with DMSO (control) or Wnt-C59 (1 μM) and growth was assessed with soft agar colony formation assay. Representative images are shown with and without Wnt-C59 treatment. The bar charts display the mean of the colony numbers of triplicate plates from a representative experiment (performed twice); Bars, standard error of the mean. ***P < 0.001 as determined using Student's t-test. (C, D) GSC11 (C) and U87MG (D) cells treated with serial doses of Wnt-C59 or control were subjected to transwell invasion assays. The data were presented as mean ± standard error of the mean. *P < 0.05, **P < 0.01, and ***P < 0.001. (E) Representative images of neurospheres of GSC11 cells after Wnt-C59 treatment. (F) The neurosphere formation efficiency was assessed in GSC11 cells. The formation assay was performed by plating dissociated single cells at a density of 1 cell/μL and counting the number of spheres that formed after 7 days. The values were mean ± standard deviation for triplicate samples. *P < 0.05 and ***P < 0.001.
(A) Representative hematoxylin-eosin staining of brains from mice four weeks post tumor implantation. U87MG and GSC11 cells were implanted into the right frontal lobes of nude mice (5 × 105 cells/mouse). TMZ was injected intraperitoneally at a dose of 82.5 mg/kg/d for 7 days, Wnt-C59 treatment was given daily by oral gavage (10 mg/kg/d) for 14 days. Wnt-C59 and TMZ suppressed tumor growth and reduced tumor diameter. Tumor diameters were quantified in hematoxylin-eosin-stained coronal sections by measuring tumor diameters at the largest cross-sectional area. The data were mean ± standard deviation. *P < 0.05 and **P < 0.01. (B) Survival analysis of mice intracranially implanted with GSC11 and U87MG cells. Athymic mice were intracranially implanted with GSC11 or U87MG cells (5 × 105 cells/mouse). Two weeks post-injection, mice were divided into four treatment groups (10 mice per group): i) control, oral saline for 14 days; ii) Wnt-C59, oral gavage (10 mg/kg/d) for 14 days; iii) TMZ, 82.5 mg/kg/d for 7 days; iv) combination of Wnt-C59 and TMZ. Combination therapy significantly increased the survival of GSC11- and U87MG-bearing animals compared with the control group and monotherapy groups. ***P < 0.001.

01/09/2025 Compuscript Ltd

Regions: Europe, Ireland, North America, United States

Keywords: Science, Life Sciences

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