TGF-α/EGFR chemotaxis drives lymphatic metastasis and early immune suppression, revealing a repositionable therapeutic target in breast cancer

TGF-α/EGFR chemotaxis drives lymphatic metastasis and early immune suppression, revealing a repositionable therapeutic target in breast cancer | 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 Research Article TGF-α/EGFR chemotaxis drives lymphatic metastasis and early immune suppression, revealing a repositionable therapeutic target in breast cancer Wenyang Shi, Yueyun Pan, Bhavik Rathod, Yuhan Wang, Zhi Wang, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7487369/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 epidermal growth factor receptor (EGFR) is a well-established oncogenic driver in multiple epithelial cancers, yet its role in breast cancer remains elusive, with EGFR-targeted therapies showing limited clinical efficacy. Here, we demonstrate that EGFR promotes selective lymphatic dissemination in triple-negative breast cancer through a chemotactic mechanism involving the EGFR ligand TGF-α. Using murine and human breast cancer models, we identify lymphatic endothelial cells (LECs) as a tumor-associated source of TGF-α, particularly upon stimulation with TGF-β1, a cytokine commonly overexpressed in breast tumors. We show that TGF-α–EGFR interactions elicit directional migration via STAT3 signaling, whereas the co-secreted ligand CTGF, enriched in blood endothelium, suppresses migration. Pharmacologic blockade of TGF-α with Fepixnebart, a first-in-class ligand-neutralizing antibody targeting TGF-α and previously not tested in oncologic indications, significantly inhibited early lymph metastasis of EGFR⁺ tumor cells. Furthermore, EGFR overexpression accelerated immune suppression in tumor-draining lymph nodes, suggesting a link between early dissemination and pre-metastatic niche formation. Together, these findings reveal an unexpected, growth-independent function for EGFR in lymph metastasis and propose a rationale for repositioning EGFR-targeted therapies toward targeting early metastatic spread and immunosuppression in breast cancer. Breast cancer EGFR lymph metastasis TGF-α Fepixnebart Full Text Additional Declarations No competing interests reported. Supplementary Files MSshietalSUPPLFIGS.pdf MSshietalSUPPLFIGSWBs.pdf 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. 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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-7487369","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":508006056,"identity":"c8e93e59-cb10-4669-be8c-2a8cdb7d5363","order_by":0,"name":"Wenyang Shi","email":"","orcid":"","institution":"Karolinska Institutet","correspondingAuthor":false,"prefix":"","firstName":"Wenyang","middleName":"","lastName":"Shi","suffix":""},{"id":508006057,"identity":"0a2c09b4-2e46-4e03-b54d-b9e37de5b7f2","order_by":1,"name":"Yueyun Pan","email":"","orcid":"","institution":"Karolinska 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