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RNA profiling from 250 UM patients identified 12 high-risk biomarkers, with RBFOX2 and COL9A3 validated by protein expression. Functional testing through COL9A3 overexpression in EIF1AXmut and BAP1mut cell lines showed enhanced motility and proliferation in BAP1mut cells and altered morphology. Zebrafish xenografts indicated increased dissemination with COL9A3 overexpression in EIF1AXmut models, while BAP1mut remained stable. RNA sequencing suggested a COL9A3-driven stress response with metabolic activation and reduced translation, followed by BAP1mut adaptation via plasticity marker upregulation (CD44, Nestin, EZH2, ABCB5, PAX3, CD166) confirmed in FFPE tissue by multiplex immunohistochemistry.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/functional-validation-of-driver-mutation-specific-uveal-melanoma-biomarkers-role-of-col9a3-in-cancer-cell-plasticity/354817/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/functional-validation-of-driver-mutation-specific-uveal-melanoma-biomarkers-role-of-col9a3-in-cancer-cell-plasticity/354817.png","ImageObject",300,407,{"name":92,"@type":93},"MrHarris58","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-23","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":24},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What is the main goal of the study described in the abstract?","Question",{"text":112,"@type":113},"To functionally validate driver mutation-specific uveal melanoma biomarkers and determine how COL9A3 influences cancer cell plasticity.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How were candidate biomarkers identified and validated?",{"text":117,"@type":113},"Twelve novel high-risk UM biomarkers were identified using RNA expression profiles from 250 patients, and the top candidates were validated at the protein expression level.",{"name":119,"@type":110,"acceptedAnswer":120},"What effects does COL9A3 show in BAP1mut versus EIF1AXmut uveal melanoma models?",{"text":121,"@type":113},"COL9A3 overexpression enhances motility and proliferation and alters morphology specifically in BAP1mut UM cells; in zebrafish xenografts, COL9A3 increases dissemination in an EIF1AXmut line while BAP1mut shows no change under wild-type conditions.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},354817,1790801077,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":24,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},687212988360,"https://ap-avatar.wpscdn.com/davatar_276721f389ce27ea32af1340a28f341c","Journal of Pathology  \nJ Pathol October 2026; 270: 226–240  \nPublished online 22 July 2026 in Wiley Online Library (wi[leyonlinelibrary.com](leyonlinelibrary.com) DOI: 10.1002/path.70094)[)](leyonlinelibrary.com) DOI: 10.1002/path.70094)[ DOI:](leyonlinelibrary.com) DOI: 10.1002/path.70094)[ 10.1002/path.70094](leyonlinelibrary.com) DOI: 10.1002/path.70094)  \nORIGINAL ARTICLE  \nFunctional validation of driver mutation-specific uveal melanoma biomarkers: role of COL9A3 in cancer cell plasticity  \nQCC van den Bosch 1,2\\#, RM Verdijk3\\#, H Fadlelseed4, TPP van den Bosch3, S Owens4, S Kennedy4, E Kilic 1$ and E Brosens2*$  \n1 Department of Ophthalmology, Erasmus MC, Rotterdam, The Netherlands  \n2 Department of Clinical Genetics, Erasmus MC Cancer Institute University Medical Center, Rotterdam, The Netherlands  \n3 Department of Pathology, Erasmus MC Cancer Institute University Medical Center, Rotterdam, The Netherlands  \n4 National Ophthalmic Pathology Laboratory, Royal Victoria Eye and Ear Hospital and Research Foundation, Dublin, Ireland  \n*Correspondence to: E Brosens, Department of Clinical Genetics, Erasmus MC Cancer Institute University Medical Center, Rotterdam, The Netherlands.  \nE-mail: [e.brosens@erasmusmc.nl](e.brosens@erasmusmc.nl)  \n\\#QCC van den Bosch and RM Verdijk shared first authorship.  \n$E Kilic and E Brosens shared last authorship.  \nAbstract  \nUveal melanoma (UM) is a deadly ocular malignancy with well-described genetic alterations that predict disease outcome. However, our current understanding of the biological underpinnings of high-risk uveal melanoma progression remains relatively limited. Using RNA expression profiles from 250 patients with UM, we identified  \n12 novel biomarkers associated with high-risk UM, with protein expression level validation of the top two candidates: the transcriptional regulator RBFOX2 and matrix protein COL9A3. Moreover, we investigated the functional contribution of COL9A3 via its overexpression in EIF1AXmut and BAP1mut UM cell lines. Our data suggest that COL9A3 enhances cell motility and cell proliferation and alters morphology specifically in BAP1mut UM cells.  \nFurthermore, zebrafish xenograft studies revealed increased cell dissemination in a EIF1AXmut UM cell line upon overexpression of COL9A3, whereas a BAP1mut UM cell line remained unchanged under wild-type conditions.  \nInterestingly, RNA sequencing revealed a high-stress profile by upregulated metabolic activity and loss of protein translation due to COL9A3 overexpression. BAP1mut UM appears to adapt to this stress by upregulation of plasticity markers, such as CD44, Nestin, EZH2, ABCB5, PAX3 and CD166, as a coping mechanism. These markers are known as differentiation markers during the development of melanocyte biogenesis and are implicated in plasticity in other high-risk cancers. The relationship between COL9A3 and plasticity was validated by multiplex immunohistochemistry of formalin-fixed paraffin-embedded (FFPE) tissue, which demonstrated colocalization of COL9A3, CD44 and Nestin. BAP1mut-UM samples presented higher levels of COL9A3, CD44 and Nestin expression than EIF1AXmut or SF3B1mut UM samples based on the mean fluorescent intensity of each marker. A positive correlation between COL9A3 and Nestin expression in triple-positive cells, irrespective of the UM subtype, was observed. Collectively, our findings suggest that COL9A3 is a novel high-risk biomarker that may contribute to UM cell plasticity and is most prevalent in BAP1mut UM.  \n© 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.  \nKeywords: uveal melanoma; COL9A3; BAP1 mutation; cell plasticity; biomarkers; tumor microenvironment; zebrafish xenograft  \nReceived 12 October 2025; Revised 24 March 2026; Accepted 7 June 2026 No conflicts of interest were declared.  \nIntroduction  \nUveal melanoma (UM) is the most common primary intraocular malignancy, with established driv","cbCailAlWnebtaqQ","https://ap.wps.com/l/cbCailAlWnebtaqQ","pdf",18699872,15,"English","# Abstract\n## Introduction\n## Role of COL9A3 in high-risk BAP1-mutant UM","[{\"question\":\"What is the main goal of the study described in the abstract?\",\"answer\":\"To functionally validate driver mutation-specific uveal melanoma biomarkers and determine how COL9A3 influences cancer cell plasticity.\"},{\"question\":\"How were candidate biomarkers identified and validated?\",\"answer\":\"Twelve novel high-risk UM biomarkers were identified using RNA expression profiles from 250 patients, and the top candidates were validated at the protein expression level.\"},{\"question\":\"What effects does COL9A3 show in BAP1mut versus EIF1AXmut uveal melanoma models?\",\"answer\":\"COL9A3 overexpression enhances motility and proliferation and alters morphology specifically in BAP1mut UM cells; in zebrafish xenografts, COL9A3 increases dissemination in an EIF1AXmut line while BAP1mut shows no change under wild-type conditions.\"}]","Functional validation of driver mutation-specific uveal melanoma biomarkers - role of COL9A3 in cancer cell plasticity | PDF",1790114174,38]