Synergistic mechanotransduction via the ΔP–EPPK1/DDR2– PI3K/AKT axis drives cell invasion and migration

Synergistic mechanotransduction via the ΔP–EPPK1/DDR2– PI3K/AKT axis drives cell invasion and migration | 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 Synergistic mechanotransduction via the ΔP–EPPK1/DDR2– PI3K/AKT axis drives cell invasion and migration Luyao Zhao, Chenhe Liu, Ruotian Du, Qigan Gao, Yuehua Yang, Yifan Han, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8929917/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 The mechanical forces within solid tumors, including solid stress and intracellular pressure, are known to contribute to the tumor microenvironment, yet how cancer cells integrate these combined cues to promote invasion is poorly understood. Here, we develop a composite in vitro model coupling cell crowding with osmotic modulation to mimic the transmembrane pressure differential (ΔP) of the tumor microenvironment. We demonstrate that crowding synergizes with hypotonic stress to elevate ΔP, which robustly enhances invasive migration. Mechanistically, ΔP activates a novel signaling axis centered on the coordinated upregulation of the cytoskeletal linker EPPK1 and the collagen receptor DDR2. This EPPK1/DDR2 hub converges on PI3K/AKT pathway activation, which in turn drives a dual pro-invasive program: upregulation of Vimentin to induce an epithelial-mesenchymal transition state and enhanced expression of MMP24 to facilitate extracellular matrix degradation. Pharmacological inhibition of either EPPK1 or DDR2 blocks ΔP-driven invasion, confirming their essential role. Our work delineates a complete mechanotransduction pathway—the ΔP-EPPK1/DDR2-PI3K/AKT-Vimentin/MMP24 axis—that translates integrated mechanical stress into invasive behavior, providing a mechanistic framework for therapeutic strategies targeting the mechanical niche of solid tumors. Biological sciences/Cancer Biological sciences/Cell biology Cell crowding Osmotic pressure Transmembrane pressure difference Invasion Migration Full Text Additional Declarations No competing interests reported. Supplementary Files Supplmethod.docx Supplfigureandlegend.docx 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. 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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-8929917","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":599776607,"identity":"d26d3e18-cbc3-419e-a127-7a5bc21f08ce","order_by":0,"name":"Luyao Zhao","email":"","orcid":"","institution":"Beihang University","correspondingAuthor":false,"prefix":"","firstName":"Luyao","middleName":"","lastName":"Zhao","suffix":""},{"id":599776608,"identity":"d0ff870b-02fd-4442-b64d-042f8bd719dd","order_by":1,"name":"Chenhe Liu","email":"","orcid":"","institution":"Beihang 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