Merlin S13 phosphorylation regulates meningioma Wnt signaling and magnetic resonance imaging features

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 use...

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Published in:Nature communications 2024-09, Vol.15 (1), p.7873
Main Authors: Eaton, Charlotte D, Avalos, Lauro, Liu, S John, Chen, Zhenhong, Zakimi, Naomi, Casey-Clyde, Tim, Bisignano, Paola, Lucas, Calixto-Hope G, Stevenson, Erica, Choudhury, Abrar, Vasudevan, Harish N, Magill, Stephen T, Young, Jacob S, Krogan, Nevan J, Villanueva-Meyer, Javier E, Swaney, Danielle L, Raleigh, David R
Format: Article
Language:English
Subjects:
Animals
beta Catenin - genetics
beta Catenin - metabolism
Biomarkers, Tumor - genetics
Biomarkers, Tumor - metabolism
Cell Line, Tumor
Female
Humans
Magnetic Resonance Imaging - methods
Male
Meningeal Neoplasms - diagnostic imaging
Meningeal Neoplasms - genetics
Meningeal Neoplasms - metabolism
Meningeal Neoplasms - pathology
Meningioma - diagnostic imaging
Meningioma - genetics
Meningioma - metabolism
Meningioma - pathology
Mice
Neurofibromin 2 - genetics
Neurofibromin 2 - metabolism
Phosphorylation
Proteomics - methods
Serine - metabolism
Wnt Signaling Pathway
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Summary: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.
ISSN:2041-1723