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Wnt activation as a therapeutic strategy in medulloblastoma
Branavan Manoranjan1,2,3, Chitra Venugopal2,4, David Bakhshinyan2,3
1Section of Neurosurgery, Department of Clinical Neurosciences, University of Calgary, Calgary, AB, T2N 1N4, Canada.
Abstract:
Medulloblastoma (MB) is defined by four molecular subgroups (Wnt, Shh, Group 3, Group 4) with Wnt MB having the most favorable prognosis. Since prior reports have illustrated the antitumorigenic role of Wnt activation in Shh MB, we aimed to assess the effects of activated canonical Wnt signaling in Group 3 and 4 MBs. By using primary patient-derived MB brain tumor-initiating cell (BTIC) lines, we characterize differences in the tumor-initiating capacity of Wnt, Group 3, and Group 4 MB. With single cell RNA-seq technology, we demonstrate the presence of rare Wnt-active cells in non-Wnt MBs, which functionally retain the impaired tumorigenic potential of Wnt MB. In treating MB xenografts with a Wnt agonist, we provide a rational therapeutic option in which the protective effects of Wnt-driven MBs may be augmented in Group 3 and 4 MB and thereby support emerging data for a context-dependent tumor suppressive role for Wnt/β-catenin signaling.
Insights
Activating Wnt signaling in medulloblastoma (MB) may suppress tumor growth. This study found Wnt-active cells in Group 3 and 4 MBs, suggesting a potential therapeutic strategy for these aggressive brain tumors.
Area of Science:
- Neuro-oncology
- Molecular biology
- Cancer research
Background:
- Medulloblastoma (MB) comprises four molecular subgroups: Wnt, Shh, Group 3, and Group 4.
- Wnt subgroup MB exhibits the most favorable prognosis.
- Prior research indicates Wnt activation has antitumorigenic effects in Shh MB.
Purpose of the Study:
- To investigate the impact of activated canonical Wnt signaling on Group 3 and Group 4 medulloblastoma.
- To compare the tumor-initiating capacity across different MB molecular subgroups.
- To explore Wnt signaling as a potential therapeutic avenue for aggressive MB subtypes.
Main Methods:
- Utilized patient-derived medulloblastoma brain tumor-initiating cell (BTIC) lines.
- Employed single-cell RNA sequencing (scRNA-seq) to analyze cellular heterogeneity.
- Treated medulloblastoma xenografts with a Wnt agonist.
Main Results:
- Identified rare Wnt-active cells within non-Wnt MB subgroups (Group 3 and Group 4).
- These Wnt-active cells demonstrated functional characteristics similar to Wnt MB, including impaired tumorigenic potential.
- Wnt agonist treatment in MB xenografts showed potential therapeutic benefits.
Conclusions:
- Wnt signaling may play a context-dependent tumor-suppressive role in Group 3 and Group 4 medulloblastoma.
- The presence of Wnt-active cells suggests a potential therapeutic strategy to augment protective Wnt effects.
- Findings support further investigation into Wnt pathway modulation for treating aggressive medulloblastoma.
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