Targeted regeneration of post-radiation epithelium without promoting cancer recurrence

Targeted regeneration of post-radiation epithelium without promoting cancer recurrence | 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 Targeted regeneration of post-radiation epithelium without promoting cancer recurrence Qiwen Gan, Ya-Wen Chen, Eric M. Genden, Michael Berger, Zhuhao Wu, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7320272/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 Cancer radiotherapy inevitably damages normal tissues, yet therapeutic activation of pro-survival or regenerative pathways frequently increases the risk of cancer recurrence. Strategies that selectively restore normal tissue without fueling malignant regrowth remain largely undefined. Using the slow dividing yet radio-responsive salivary gland and adjacent oral squamous cell carcinoma (OSCC) as paired in vivo models, we established a high-throughput genetic screening platform to quantify post-irradiation clonal expansion in both normal and malignant epithelium. Comparative screening revealed depletion of the salivary gland dominant SWI/SNF core ATPase Smarca2 as the top-ranking selective driver of salivary epithelial regeneration, in contrast to most candidates that promoted expansion in both tissues. Smarca2 depletion specifically enhanced regeneration of acinar cells, the lineage most refractory to recovery after irradiation, by suppressing terminal differentiation programs and enabling transcriptional activation of key regenerative genes. In OSCC cells, however, this regenerative switch was uncoupled from Smarca2 depletion due to tumor-specific chromatin state remodeling. Notably, this mechanism is conserved in human salivary gland tissue and can be induced using SMARCA2-targeting PROTAC degrader, a therapeutic class under active development for cancer treatment. Together, our findings suggest that Smarca2 depletion is a potent lineage-specific mechanism to replenish radiation damaged salivary epithelium without promoting OSCC expansion, a paradigm that is underexplored. Biological sciences/Cancer/Oral cancer Biological sciences/Stem cells/Regeneration Full Text Additional Declarations There is NO Competing Interest. 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-7320272","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":592723075,"identity":"a29fc991-0a42-4ce2-a057-ec5df00d0351","order_by":0,"name":"Qiwen Gan","email":"","orcid":"https://orcid.org/0000-0001-8945-5930","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Qiwen","middleName":"","lastName":"Gan","suffix":""},{"id":592723076,"identity":"317ea6ae-39bf-4b0b-983f-102815a220b6","order_by":1,"name":"Ya-Wen Chen","email":"","orcid":"https://orcid.org/0000-0003-2382-8444","institution":"Icahn School of Medicine at Mount Sinai","correspondingAuthor":false,"prefix":"","firstName":"Ya-Wen","middleName":"","lastName":"Chen","suffix":""},{"id":592723077,"identity":"4572f533-21fa-4312-941f-b20f53289afb","order_by":2,"name":"Eric M. 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