TMEM216 inhibits breast cancer lung metastasis by modulating IGF1R-IRS4 signaling pathway

TMEM216 inhibits breast cancer lung metastasis by modulating IGF1R-IRS4 signaling pathway | 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 TMEM216 inhibits breast cancer lung metastasis by modulating IGF1R-IRS4 signaling pathway Xiangguo Liu, Yingying Wang, Xinyang Bai, zhiyuan Du, Jiaxi Dong, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6101684/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Breast cancer (BrCa) metastasis remains a major cause of mortality, yet the molecular mechanisms driving this process are incompletely understood. This study identifies TMEM216, a transmembrane protein implicated in ciliary homeostasis, as a novel suppressor of lung metastasis in BrCa. Using mammary-specific Tmem216 knockout mice, we demonstrate that Tmem216 deficiency promotes lung metastasis without affecting primary tumor proliferation. Clinical analyses reveal reduced TMEM216 expression in metastatic lesions and aggressive cell lines, correlating with poor patient distant metastasis-free survival. Mechanistically, TMEM216 interacts with IGF1R and binds to IRS4 via the conserved K79-D1049 interaction, disrupting the IGF1R-IRS4 complex formation and suppressing IGF pathway activation. Rescue experiments in vitro and in vivo confirm that TMEM216-mediated metastasis inhibition depends on IGF signaling modulation. Tissue microarray analyses further establish an inverse correlation between TMEM216 levels and IGF1R phosphorylation in BrCa patients, with low TMEM216 expression associated with advanced metastasis. These findings delineate TMEM216 as a critical regulator of the IGF1R-IRS4 axis, offering therapeutic opportunities for targeting metastatic BrCa. Biological sciences/Cancer/Breast cancer Biological sciences/Cell biology/Cell migration TMEM216 IGF1R IRS4 breast cancer metastasis Full Text Additional Declarations There is NO Competing Interest. Supplementary Files TMEM216BrCaSupplementaryMaterial20250225.pdf Supplementary Material Cite Share Download PDF Status: Under Review 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. 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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-6101684","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":427143593,"identity":"2ee7a86d-cf6a-4ea7-b2bf-b97149e39747","order_by":0,"name":"Xiangguo 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