The Wnt signaling networks in higher-grade meningiomas: from molecular pathogenesis to therapeutic innovation.

Meningiomas are the most frequently reported primary brain and other central nervous system tumors and account for more than one-third of all primary CNS tumors. High-grade meningiomas (WHO grades 2 and 3) are associated with significantly poorer prognosis and a higher risk of recurrence than grade 1 tumors, despite surgery and radiotherapy. Although several genetic and epigenetic alterations, including NF2 inactivation and related molecular drivers, have been identified in these tumors, effective systemic treatment options remain limited. Increasing evidence indicates that the Wnt/β-catenin signaling pathway is altered in meningiomas, as demonstrated by dysregulated expression of β-catenin, pathway regulators, and downstream transcriptional activity in different studies. Mechanistic studies in meningioma models show that Merlin S13 dephosphorylation, rather than Merlin loss alone, can attenuate inhibitory Merlin-β-catenin interactions, promote β-catenin-dependent Wnt signaling, and support tumor growth in NF2-wildtype meningiomas. Because the Wnt pathway regulates key processes such as proliferation, differentiation, apoptosis resistance, and tumor microenvironment interactions, its dysregulation may contribute to meningioma progression, particularly in biologically aggressive or higher-grade tumors. A better understanding of these mechanisms may help identify more rational therapeutic approaches for aggressive meningiomas. However, their clinical relevance will depend on whether candidate strategies can achieve adequate tumor exposure while maintaining acceptable systemic and CNS safety.