MerlinS13 phosphorylation regulates meningioma Wnt signaling and magnetic resonance imaging features

• Published in: Nature communications 2024-09, Vol.15 (1), p.7873-14, Article 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: 45/91; 631/67/1922; 631/80/458/1733; 631/80/86/2370; Biomarkers; Clinical outcomes; Dephosphorylation; Diffusion coefficient; Functional magnetic resonance imaging; Gene sequencing; Humanities and Social Sciences; Inactivation; Magnetic resonance imaging; Mass spectrometry; Mass spectroscopy; Medical imaging; Meningioma; Molecular modelling; multidisciplinary; Neurofibromin 2; Patients; Phosphorylation; Proteomics; Science; Science (multidisciplinary); Serine; Signal transduction; Surveillance; Tumors; Wnt protein; Xenotransplantation; β-Catenin
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-52284-8

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. The molecular mechanisms underlying merlin-intact meningioma growth remain to be explored. Here, the authors show that merlin activates Wnt signalling and tumour growth through its dephosphorylation on serine 13 attenuating the inhibitory interactions with β-catenin.