MerlinS13 phosphorylation regulates meningioma Wnt signaling and magnetic resonance imaging features

Charlotte D. Eaton, Lauro Avalos, S. John Liu, Zhenhong Chen, Naomi Zakimi, Tim Casey-Clyde, Paola Bisignano, Calixto-Hope G. Lucas, Erica Stevenson, Abrar Choudhury, Harish N. Vasudevan, Stephen T. Magill, Jacob S. Young, Nevan J. Krogan, Javier E. Villanueva-Meyer, Danielle L. Swaney and David R. Raleigh ()
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Charlotte D. Eaton: University of California San Francisco
Lauro Avalos: University of California San Francisco
S. John Liu: University of California San Francisco
Zhenhong Chen: University of California San Francisco
Naomi Zakimi: University of California San Francisco
Tim Casey-Clyde: University of California San Francisco
Paola Bisignano: Vanderbilt University
Calixto-Hope G. Lucas: Johns Hopkins University
Erica Stevenson: California Institute for Quantitative Biosciences
Abrar Choudhury: University of California San Francisco
Harish N. Vasudevan: University of California San Francisco
Stephen T. Magill: Northwestern University
Jacob S. Young: University of California San Francisco
Nevan J. Krogan: California Institute for Quantitative Biosciences
Javier E. Villanueva-Meyer: University of California San Francisco
Danielle L. Swaney: California Institute for Quantitative Biosciences
David R. Raleigh: University of California San Francisco

Nature Communications, 2024, vol. 15, issue 1, 1-14

Abstract: Abstract 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.

Date: 2024
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DOI: 10.1038/s41467-024-52284-8

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