Gamma-synuclein promotes Bevacizumab resistance by activating vascular endothelial growth factor receptor in colorectal cancer

Gamma-synuclein promotes Bevacizumab resistance by activating vascular endothelial growth factor receptor in colorectal 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 Article Gamma-synuclein promotes Bevacizumab resistance by activating vascular endothelial growth factor receptor in colorectal cancer Caiyun liu, Lixin Wang, Bin Dong, Lin Meng, Like Qu, Chuanke Zhao, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5414606/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 Resistance to Bevacizumab (Bev) is emerging as a major clinical problem. Gamma-synuclein (SNCG) is overexpressed in the tumor vasculature and various cancer cells. There are no studies on the role of SNCG in Bev resistance. Here, we analyzed the effect of SNCG on Bev resistance in vitro and in vivo, assessed the impact of combining an anti-SNCG monoclonal antibody (McAb, 42#) with Bev on mouse xenograft models derived from HT29 cells with intrinsic resistance to Bev, and explored the mechanism of SNCG-regulated Bev therapy resistance. We found that SNCG overexpression induced tumor resistance to Bev, while SNCG knockout restored sensitivity to Bev by inhibiting both vascularization and SNCG-vascular endothelial growth factor receptor (VEGFR) signaling pathway. Interestingly, SNCG activated VEGFR2, whereas SNCG expression was upregulated after Bev treatment, thus generating a reciprocal feedback between SNCG and Bev, which in turn promoted Bev treatment resistance. Importantly, combining Bev with 42# significantly blocked tumor growth, impeded distant tumor metastasis, and extended mouse survival time by reducing vessel formation and decreasing the levels of SNCG-VEGFR2 signaling pathway proteins in Bev-resistant xenograft models. Our findings provide a theoretical basis to overcome Bev resistance by combining Bev with anti-SNCG antibodies in colorectal cancer (CRC). Biological sciences/Cancer/Gastrointestinal cancer/Colorectal cancer Biological sciences/Drug discovery/Target validation gamma-synuclein (SNCG) Bevacizumab (Bev) resistance colorectal cancer (CRC) vascular endothelial growth factor receptor (VEGFR) angiogenesis Full Text Additional Declarations There is NO conflict of interest to disclose. Supplementary Files supplementarymaterials.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. 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-5414606","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":375960122,"identity":"35b5480e-1281-4945-9aaa-404d93ff4ed3","order_by":0,"name":"Caiyun 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Gamma-synuclein (SNCG) is overexpressed in the tumor vasculature and various cancer cells. There are no studies on the role of SNCG in Bev resistance. Here, we analyzed the effect of SNCG on Bev resistance in vitro and in vivo, assessed the impact of combining an anti-SNCG monoclonal antibody (McAb, 42#) with Bev on mouse xenograft models derived from HT29 cells with intrinsic resistance to Bev, and explored the mechanism of SNCG-regulated Bev therapy resistance. We found that SNCG overexpression induced tumor resistance to Bev, while SNCG knockout restored sensitivity to Bev by inhibiting both vascularization and SNCG-vascular endothelial growth factor receptor (VEGFR) signaling pathway. Interestingly, SNCG activated VEGFR2, whereas SNCG expression was upregulated after Bev treatment, thus generating a reciprocal feedback between SNCG and Bev, which in turn promoted Bev treatment resistance. Importantly, combining Bev with 42# significantly blocked tumor growth, impeded distant tumor metastasis, and extended mouse survival time by reducing vessel formation and decreasing the levels of SNCG-VEGFR2 signaling pathway proteins in Bev-resistant xenograft models. 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