MerlinS13 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 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.
Authors
- Calixto‐Hope G. Lucas (ORCID: https://orcid.org/0000-0002-8347-9592)
- Jacob S. Young (ORCID: https://orcid.org/0000-0002-5499-4325)
- David Ronan Raleigh (ORCID: https://orcid.org/0000-0001-9299-8864)
- Nevan J. Krogan (ORCID: https://orcid.org/0000-0003-4902-337X)
- Tim Casey-Clyde
- Charlotte Eaton (ORCID: https://orcid.org/0009-0008-1624-2561)
- Stephen T. Magill (ORCID: https://orcid.org/0000-0002-5257-7835)
- Zhenhong Chen
- Javier Villanueva-Meyer (ORCID: https://orcid.org/0000-0002-5910-0757)
- Paola Bisignano (ORCID: https://orcid.org/0000-0003-1789-762X)
- Lauro N. Avalos
- Erica Stevenson (ORCID: https://orcid.org/0000-0001-7853-1854)
- Harish N. Vasudevan (ORCID: https://orcid.org/0000-0001-9633-1100)
- Abrar Choudhury (ORCID: https://orcid.org/0000-0001-8312-2457)
- Danielle L. Swaney (ORCID: https://orcid.org/0000-0001-6119-6084)
- Naomi Zakimi
- Siyuan Liu (ORCID: https://orcid.org/0000-0003-1042-0191)
Institutions
- QB3 (US)
- Northwestern University (US)
- Gladstone Institutes (US)
- Johns Hopkins University (US)
- University of California, San Francisco (US)
- Vanderbilt University (US)
- University of California System (US)
- Neurological Surgery (US)
- University of San Francisco (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-09-09
- DOI
- https://doi.org/10.1038/s41467-024-52284-8
- Citations
- 4
- Primary Topic
- Meningioma and schwannoma management
- Type
- article
- Field-Weighted Citation Impact
- 1.55
Funders
- Northwestern University
- National Institutes of Health
- University of California, San Francisco
- Robert H. Lurie Comprehensive Cancer Center