Meningiomas are associated with inactivation of NF2/Merlin, but approximately one-third of meningiomas with favorable clinical outcomes retain Merlin expression. Biochemical mechanisms underlying Merlin-intact meningioma growth are incompletely understood, and non-invasive biomarkers that may be used to guide treatment de-escalation or imaging surveillance are lacking. Here, we use single-cell RNA sequencing, proximity-labeling proteomic mass spectrometry, mechanistic and functional approaches, and magnetic resonance imaging (MRI) across meningioma xenografts and patients to define biochemical mechanisms and an imaging biomarker that underlie Merlin-intact meningiomas. We find Merlin serine 13 (S13) dephosphorylation drives meningioma Wnt signaling and tumor growth by attenuating inhibitory interactions with β-catenin and activating the Wnt pathway. MRI analyses show Merlin-intact meningiomas with S13 phosphorylation and favorable clinical outcomes are associated with high apparent diffusion coefficient (ADC). These results define mechanisms underlying a potential imaging biomarker that could be used to guide treatment de-escalation or imaging surveillance for patients with Merlin-intact meningiomas.

脑膜瘤与 NF2/Merlin 的失活有关，但大约 1/3 具有良好临床结果的脑膜瘤保留了 Merlin 表达。Merlin 完整脑膜瘤生长的生化机制尚不完全清楚，并且缺乏可用于指导治疗降级或影像学监测的非侵入性生物标志物。在这里，我们使用单细胞 RNA 测序、邻近标记蛋白质组学质谱、机制和功能方法以及跨脑膜瘤异种移植物和患者的磁共振成像 （MRI） 来确定生化机制和成像生物标志物，这些机制是 Merlin 完整脑膜瘤的基础。我们发现 Merlin 丝氨酸 13 （S13） 去磷酸化通过减弱与 β-catenin 的抑制性相互作用并激活 Wnt 通路来驱动脑膜瘤 Wnt 信号传导和肿瘤生长。MRI 分析显示，具有 S13 磷酸化和良好临床结果的 Merlin 完整脑膜瘤与高表观弥散系数 （ADC） 相关。这些结果定义了潜在影像学生物标志物的潜在机制，可用于指导 Merlin 完整脑膜瘤患者的治疗降级或影像学监测。