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Nevertheless, the mechanisms underlying KRAS\n \n G12D<\/jats:sup>\n <\/jats:italic>\n \/TP53\n \n R175H<\/jats:sup>\n <\/jats:italic>\n co\u2010mutation\u2010mediated LN metastasis remain unclear. Herein, we developed KRAS\n \n G12D<\/jats:sup>\n <\/jats:italic>\n \/TP53\n \n R175H<\/jats:sup>\n <\/jats:italic>\n mutation\u2010related orthotopic xenograft models and demonstrated that KRAS\n \n G12D<\/jats:sup>\n <\/jats:italic>\n \/TP53\n \n R175H<\/jats:sup>\n <\/jats:italic>\n co\u2010mutation promotes the lymphangiogenesis and LN metastasis. FUS is identified by next generation sequencing to be upregulated in tumor tissues harbouring KRAS\n \n G12D<\/jats:sup>\n <\/jats:italic>\n \/TP53\n \n R175H<\/jats:sup>\n <\/jats:italic>\n co\u2010mutation across multi\u2010center cohorts, wherein KRAS\n \n G12D<\/jats:sup>\n <\/jats:italic>\n \u2010mediated phosphorylation of TP53\n \n R175H<\/jats:sup>\n <\/jats:italic>\n promotes FUS transcriptional activation. Functionally, FUS\u2010mediated extracellular vesicle (EV) promotes lymphangiogenesis and LN metastasis\n in vitro<\/jats:italic>\n and\n in vivo<\/jats:italic>\n . Mechanistically, upon KRAS\n \n \n G12D<\/jats:italic>\n <\/jats:sup>\n <\/jats:italic>\n \/TP53\n \n \n R175H<\/jats:italic>\n <\/jats:sup>\n <\/jats:italic>\n co \u2011 mutation, FUS regulated circSCARNA10 biosynthesis and promotes EVs secretion by stabilizing RAB3B mRNA, leading to VEGFR3 transcription in lymphatic endothelial cells to trigger lymphangiogenesis and LN metastasis. Blockade of FUS inhibits LN metastasis in Kras\n \n G12D\/+<\/jats:sup>\n <\/jats:italic>\n Trp53\n \n R172H\/+<\/jats:sup>\n <\/jats:italic>\n Pdx\u20101\u2010Cre (KPC) mice model. Clinically, detecting circSCARNA10 in serum\u2010EVs exhibited higher diagnostic efficiency compared with traditional biomarkers, carcinoembryonic antigen (CEA) and carbohydrate antigen 19\u20109 (CA19\u20109) in distinguishing LN metastasis. Collectively, we highlight the precise mechanisms by which KRAS\n \n G12D<\/jats:sup>\n <\/jats:italic>\n \/TP53\n \n R175H<\/jats:sup>\n <\/jats:italic>\n co\u2010mutation mediates EV secretion to trigger LN metastasis, providing a potential therapeutic target for KRAS\n \n G12D<\/jats:sup>\n <\/jats:italic>\n \/TP53\n \n R175H<\/jats:sup>\n <\/jats:italic>\n co\u2010mutation \u2010 driven LN metastasis.\n <\/jats:p>","DOI":"10.1002\/jev2.70383","type":"journal-article","created":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T17:14:46Z","timestamp":1791652486000},"source":"Crossref","is-referenced-by-count":0,"title":["MVB Maturation Responsive to KRAS\n G12D<\/sup>\n \/TP53\n R175H<\/sup>\n Co\u2010mutations Fuels Extracellular Vesicle\u2010hypersecretion Phenotype to Aggravate Lymphangiogenesis and Lymphatic Metastasis"],"prefix":"10.1002","volume":"15","author":[{"given":"Jiabin","family":"Yang","sequence":"first","affiliation":[{"name":"Department of Pancreatic Surgery Department of General Surgery Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou Guangdong PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuming","family":"Luo","sequence":"additional","affiliation":[{"name":"Department of Pancreatic Surgery Department of General Surgery Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou Guangdong PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pancreatic Surgery Department of General Surgery Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University Guangzhou Guangdong PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingjie","family":"An","sequence":"additional","affiliation":[{"name":"Department of Urology Sun Yat\u2010sen Memorial Hospital Sun Yat\u2010sen University Guangzhou Guangdong PR China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation State Key Laboratory of Oncology in South China Sun Yat\u2010sen Memorial Hospital Guangzhou Guangdong PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingrui","family":"Pang","sequence":"additional","affiliation":[{"name":"Department of Urology Sun Yat\u2010sen Memorial Hospital Sun Yat\u2010sen University Guangzhou Guangdong PR China"},{"name":"Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation State Key Laboratory of Oncology in South China Sun Yat\u2010sen Memorial Hospital Guangzhou Guangdong PR China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhihua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Oncology Sun Yat\u2010sen Memorial Hospital Sun Yat\u2010sen University Guangzhou Guangdong 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