N-Cadherin Dynamically Regulates Schwannoma Migration and Represents a Novel Therapeutic Target in NF2-Related Schwannomatosis

N-Cadherin Dynamically Regulates Schwannoma Migration and Represents a Novel Therapeutic Target in NF2-Related Schwannomatosis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article N-Cadherin Dynamically Regulates Schwannoma Migration and Represents a Novel Therapeutic Target in NF2-Related Schwannomatosis Yin Ren, Han Nguyen, Melanie Fisher, Ruiqi Zhou, Taha Jan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8817797/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract NF2-related schwannomatosis (NF2-SWN) is a devastating tumor predisposition syndrome marked by multiple schwannomas and substantial morbidity. Vestibular Schwannoma (VS), the hallmark tumor, causes deafness, vertigo and potentially fatal brainstem compression. A subset develops brainstem adhesions, making surgery - the only treatment option – highly risky in the absence of FDA-approved therapies. During NF2-SWN progression, schwannoma cells migrate from the extracellular matrix (ECM)-rich internal auditory canal to the arachnoid-lined brainstem, yet mechanisms driving this transition remain incompletely defined. We previously demonstrated that adherent schwannoma is associated with elevated matrix metalloproteinase-9 (MMP-9) activity. N-cadherin (N-cad), a key cell-matrix adhesion molecule and regulator of cancer cell migration, has not been studied in NF2-SWN. Integrating RNA sequencing, multiple NF2 schwannoma mouse models and primary human VS cultures, we demonstrate that N-cad is overexpressed in sporadic and NF2-associated VS. N-cad differentially regulates VS spheroid migration – promoting motility on astrocytes but restraining on ECM. MMP-9 cleaves N-cad to drive schwannoma proliferation through IL-6/STAT3 and NF-κB signaling. Pharmacologic and genetic inhibition of N-cad synergized with dasatinib and brigatinib, two kinase inhibitors with efficacy in NF2-SWN, to suppress schwannoma proliferation and tumor growth. These findings establish N-cad as a central regulator of schwannoma migration and a novel therapeutic target. Biological sciences/Cell biology/Cell migration/Focal adhesion Biological sciences/Cell biology/Cell adhesion/Cadherins Full Text Additional Declarations There is NO conflict of interest to disclose. Supplementary Files Supplementaryinformation.pdf Supplementary information Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8817797","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":592832189,"identity":"c44e4c53-bf5b-4db8-b95a-21571dc4a315","order_by":0,"name":"Yin Ren","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAv0lEQVRIie3LIQvCQBjG8VcOtJxeXph+hRvDJfGzbAhb2aosGJZMQ+v2LZbMBy+YDqwbWkTwM1xSGTKw3UXD/ePD8wOw2f4wjgBEAcyHYVQYEQrgmxOn+JJoeOoJm0wFofktOTK5bBSs3EZoyJjMQqLkM6urNOhKiH0DQjm57zFrWhpcATAyI94LE36RPXkbEqfAkIu0J8KMID2jV1fxtiv5xq+1hEnvQXe4YAxPrcrX7kFH+n4+3OBus9lsNn0fbDVAeqkp/vYAAAAASUVORK5CYII=","orcid":"","institution":"The Ohio State University Wexner Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Yin","middleName":"","lastName":"Ren","suffix":""},{"id":592832190,"identity":"9c985373-14b6-4add-a87f-93006600a1b4","order_by":1,"name":"Han Nguyen","email":"","orcid":"","institution":"The Ohio State University Wexner Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Han","middleName":"","lastName":"Nguyen","suffix":""},{"id":592832191,"identity":"783ba1b4-373d-45aa-87ce-b2a83b805d13","order_by":2,"name":"Melanie Fisher","email":"","orcid":"","institution":"The Ohio State University Wexner Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Melanie","middleName":"","lastName":"Fisher","suffix":""},{"id":592832192,"identity":"dfec7709-4432-44ff-b704-f573271c07a3","order_by":3,"name":"Ruiqi Zhou","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Ruiqi","middleName":"","lastName":"Zhou","suffix":""},{"id":592832193,"identity":"b018aaf4-c6b9-495a-a7c6-bde9790391ab","order_by":4,"name":"Taha Jan","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Taha","middleName":"","lastName":"Jan","suffix":""}],"badges":[],"createdAt":"2026-02-07 19:55:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8817797/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8817797/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":105727899,"identity":"d42c79f1-a9bb-409e-b9f1-3c9fd56d8512","added_by":"auto","created_at":"2026-03-30 11:05:17","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1866986,"visible":true,"origin":"","legend":"Article File","description":"","filename":"MergedFile.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8817797/v1_covered_c755c387-a51e-40a9-91e4-7cf7a592dca6.pdf"},{"id":103004487,"identity":"aa1c8250-baa5-4bc3-8a90-17829e607731","added_by":"auto","created_at":"2026-02-19 14:40:32","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":1076955,"visible":true,"origin":"","legend":"Supplementary information","description":"","filename":"Supplementaryinformation.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8817797/v1/4955d0e269ce04ba9b6712ed.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e conflict of interest to disclose.","formattedTitle":"N-Cadherin Dynamically Regulates Schwannoma Migration and Represents a Novel Therapeutic Target in NF2-Related Schwannomatosis","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8817797/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8817797/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"NF2-related schwannomatosis (NF2-SWN) is a devastating tumor predisposition syndrome marked by multiple schwannomas and substantial morbidity. Vestibular Schwannoma (VS), the hallmark tumor, causes deafness, vertigo and potentially fatal brainstem compression. A subset develops brainstem adhesions, making surgery - the only treatment option – highly risky in the absence of FDA-approved therapies. During NF2-SWN progression, schwannoma cells migrate from the extracellular matrix (ECM)-rich internal auditory canal to the arachnoid-lined brainstem, yet mechanisms driving this transition remain incompletely defined. We previously demonstrated that adherent schwannoma is associated with elevated matrix metalloproteinase-9 (MMP-9) activity. N-cadherin (N-cad), a key cell-matrix adhesion molecule and regulator of cancer cell migration, has not been studied in NF2-SWN. Integrating RNA sequencing, multiple NF2 schwannoma mouse models and primary human VS cultures, we demonstrate that N-cad is overexpressed in sporadic and NF2-associated VS. 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