{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T16:01:15Z","timestamp":1789488075176,"version":"build-2803163510"},"reference-count":56,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100010318","name":"Landelijke Stichting voor Blinden en Slechtzienden","doi-asserted-by":"publisher","award":["2019\u20107"],"award-info":[{"award-number":["2019\u20107"]}],"id":[{"id":"10.13039\/501100010318","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010372","name":"Rotterdamse Stichting Blindenbelangen","doi-asserted-by":"publisher","award":["HV\/AB\/B20200043"],"award-info":[{"award-number":["HV\/AB\/B20200043"]}],"id":[{"id":"10.13039\/501100010372","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010302","name":"Algemene Nederlandse Vereniging ter voorkoming van Blindheid","doi-asserted-by":"publisher","award":["2019\u201007"],"award-info":[{"award-number":["2019\u201007"]}],"id":[{"id":"10.13039\/501100010302","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["pathsocjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Pathology"],"published-print":{"date-parts":[[2026,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>\n                    Uveal melanoma (UM) is a deadly ocular malignancy with well\u2010described genetic alterations that predict disease outcome. However, our current understanding of the biological underpinnings of high\u2010risk uveal melanoma progression remains relatively limited. Using RNA expression profiles from 250 patients with UM, we identified 12 novel biomarkers associated with high\u2010risk UM, with protein expression level validation of the top two candidates: the transcriptional regulator\n                    <jats:italic>RBFOX2<\/jats:italic>\n                    and matrix protein\n                    <jats:italic>COL9A3<\/jats:italic>\n                    . Moreover, we investigated the functional contribution of COL9A3 via its overexpression in\n                    <jats:italic>EIF1AX<\/jats:italic>\n                    <jats:sup>mut<\/jats:sup>\n                    and\n                    <jats:italic>BAP1<\/jats:italic>\n                    <jats:sup>mut<\/jats:sup>\n                    UM cell lines. Our data suggest that COL9A3 enhances cell motility and cell proliferation and alters morphology specifically in\n                    <jats:italic>BAP1<\/jats:italic>\n                    <jats:sup>mut<\/jats:sup>\n                    UM cells. Furthermore, zebrafish xenograft studies revealed increased cell dissemination in a\n                    <jats:italic>EIF1AX<\/jats:italic>\n                    <jats:sup>mut<\/jats:sup>\n                    UM cell line upon overexpression of COL9A3, whereas a\n                    <jats:italic>BAP1<\/jats:italic>\n                    <jats:sup>mut<\/jats:sup>\n                    UM cell line remained unchanged under wild\u2010type conditions. Interestingly, RNA sequencing revealed a high\u2010stress profile by upregulated metabolic activity and loss of protein translation due to COL9A3 overexpression.\n                    <jats:italic>BAP1<\/jats:italic>\n                    <jats:sup>mut<\/jats:sup>\n                    UM appears to adapt to this stress by upregulation of plasticity markers, such as\n                    <jats:italic>CD44<\/jats:italic>\n                    ,\n                    <jats:italic>Nestin<\/jats:italic>\n                    ,\n                    <jats:italic>EZH2<\/jats:italic>\n                    ,\n                    <jats:italic>ABCB5<\/jats:italic>\n                    ,\n                    <jats:italic>PAX3<\/jats:italic>\n                    and\n                    <jats:italic>CD166<\/jats:italic>\n                    , 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\u2010risk cancers. The relationship between COL9A3 and plasticity was validated by multiplex immunohistochemistry of formalin\u2010fixed paraffin\u2010embedded (FFPE) tissue, which demonstrated colocalization of COL9A3, CD44 and Nestin.\n                    <jats:italic>BAP1<\/jats:italic>\n                    <jats:sup>mut<\/jats:sup>\n                    \u2010UM samples presented higher levels of COL9A3, CD44 and Nestin expression than\n                    <jats:italic>EIF1AX<\/jats:italic>\n                    <jats:sup>mut<\/jats:sup>\n                    or\n                    <jats:italic>SF3B1<\/jats:italic>\n                    <jats:sup>mut<\/jats:sup>\n                    UM samples based on the mean fluorescent intensity of each marker. A positive correlation between COL9A3 and Nestin expression in triple\u2010positive cells, irrespective of the UM subtype, was observed. Collectively, our findings suggest that COL9A3 is a novel high\u2010risk biomarker that may contribute to UM cell plasticity and is most prevalent in\n                    <jats:italic>BAP1<\/jats:italic>\n                    <jats:sup>mut<\/jats:sup>\n                    UM. \u00a9 2026 The Author(s).\n                    <jats:italic>The Journal of Pathology<\/jats:italic>\n                    published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70094","type":"journal-article","created":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T06:17:22Z","timestamp":1784701042000},"page":"226-240","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Functional validation of driver mutation\u2010specific uveal melanoma biomarkers: role of\n                    <scp>COL9A3<\/scp>\n                    in cancer cell plasticity"],"prefix":"10.1002","volume":"270","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-3675-6006","authenticated-orcid":false,"given":"QCC","family":"van den Bosch","sequence":"first","affiliation":[{"name":"Department of Ophthalmology Erasmus MC  Rotterdam The Netherlands"},{"name":"Department of Clinical Genetics Erasmus MC Cancer Institute University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1437-214X","authenticated-orcid":false,"given":"RM","family":"Verdijk","sequence":"additional","affiliation":[{"name":"Department of Pathology Erasmus MC Cancer Institute University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8850-5163","authenticated-orcid":false,"given":"H","family":"Fadlelseed","sequence":"additional","affiliation":[{"name":"National Ophthalmic Pathology Laboratory Royal Victoria Eye and Ear Hospital and Research Foundation  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7223-4565","authenticated-orcid":false,"given":"TPP","family":"van den Bosch","sequence":"additional","affiliation":[{"name":"Department of Pathology Erasmus MC Cancer Institute University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5420-4154","authenticated-orcid":false,"given":"S","family":"Owens","sequence":"additional","affiliation":[{"name":"National Ophthalmic Pathology Laboratory Royal Victoria Eye and Ear Hospital and Research Foundation  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4948-5374","authenticated-orcid":false,"given":"S","family":"Kennedy","sequence":"additional","affiliation":[{"name":"National Ophthalmic Pathology Laboratory Royal Victoria Eye and Ear Hospital and Research Foundation  Dublin Ireland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6867-3792","authenticated-orcid":false,"given":"E","family":"Kilic","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology Erasmus MC  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8235-4010","authenticated-orcid":false,"given":"E","family":"Brosens","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics Erasmus MC Cancer Institute University Medical Center  Rotterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41572-020-0158-0"},{"key":"e_1_2_8_3_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.03-0538"},{"key":"e_1_2_8_4_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2304753"},{"key":"e_1_2_8_5_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbcan.2023.189055"},{"key":"e_1_2_8_6_1","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-21-1059"},{"key":"e_1_2_8_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/nature07586"},{"key":"e_1_2_8_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2017.259"},{"key":"e_1_2_8_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng.2674"},{"key":"e_1_2_8_10_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1194472"},{"key":"e_1_2_8_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2016.01.023"},{"key":"e_1_2_8_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2017.07.003"},{"key":"e_1_2_8_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-021-03964-8"},{"key":"e_1_2_8_14_1","doi-asserted-by":"publisher","DOI":"10.1101\/gr.275308.121"},{"key":"e_1_2_8_15_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers14153668"},{"key":"e_1_2_8_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2023.113132"},{"key":"e_1_2_8_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2011.551"},{"key":"e_1_2_8_18_1","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11060815"},{"key":"e_1_2_8_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2017.09.007"},{"key":"e_1_2_8_20_1","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-10-0605"},{"key":"e_1_2_8_21_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn764"},{"key":"e_1_2_8_22_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.08-2033"},{"key":"e_1_2_8_23_1","doi-asserted-by":"publisher","DOI":"10.1177\/117693510700300022"},{"key":"e_1_2_8_24_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ophtha.2012.02.017"},{"key":"e_1_2_8_25_1","doi-asserted-by":"publisher","DOI":"10.1089\/106652702760138592"},{"key":"e_1_2_8_26_1","doi-asserted-by":"publisher","DOI":"10.1198\/016214502753479248"},{"key":"e_1_2_8_27_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.211566398"},{"key":"e_1_2_8_28_1","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910620208"},{"key":"e_1_2_8_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molonc.2014.06.004"},{"key":"e_1_2_8_30_1","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_2_8_31_1","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.65.10.26"},{"key":"e_1_2_8_32_1","doi-asserted-by":"publisher","DOI":"10.1080\/15476286.2016.1259781"},{"key":"e_1_2_8_33_1","doi-asserted-by":"publisher","DOI":"10.2147\/OTT.S284262"},{"key":"e_1_2_8_34_1","unstructured":"van denBoschQCC NguyenJQN KonemannN et al.Transcriptional regulators FOXD1 and RBFOX2 contribute to metastatic capacity inBAP1mutuveal melanoma.bioRxiv2025: 2025.2004.2014.648661. [Not peer reviewed]."},{"key":"e_1_2_8_35_1","doi-asserted-by":"publisher","DOI":"10.1111\/iep.12011"},{"key":"e_1_2_8_36_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M409412200"},{"key":"e_1_2_8_37_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41431-021-00820-1"},{"key":"e_1_2_8_38_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.36165"},{"key":"e_1_2_8_39_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.heliyon.2024.e36164"},{"key":"e_1_2_8_40_1","doi-asserted-by":"publisher","DOI":"10.1155\/2023\/9942663"},{"key":"e_1_2_8_41_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11418-021-01505-1"},{"key":"e_1_2_8_42_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-021-04460-7"},{"key":"e_1_2_8_43_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.1098800"},{"key":"e_1_2_8_44_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12920-021-00928-9"},{"key":"e_1_2_8_45_1","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.2013.326"},{"key":"e_1_2_8_46_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12935-019-0884-0"},{"key":"e_1_2_8_47_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1000293107"},{"key":"e_1_2_8_48_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.biomaterials.2017.03.008"},{"key":"e_1_2_8_49_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-4182(04)80013-9"},{"key":"e_1_2_8_50_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13046-019-1270-4"},{"key":"e_1_2_8_51_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cub.2007.10.034"},{"key":"e_1_2_8_52_1","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3459"},{"key":"e_1_2_8_53_1","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26199745"},{"key":"e_1_2_8_54_1","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(19970401)79:7<1299::AID-CNCR5>3.0.CO;2-C"},{"key":"e_1_2_8_55_1","first-page":"1885","article-title":"Amino\u2010terminal propeptide of type III procollagen: a new prognosis indicator in human ovarian cancer","volume":"49","author":"Kauppila A","year":"1989","journal-title":"Cancer Res"},{"key":"e_1_2_8_56_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2020.575569"},{"key":"e_1_2_8_57_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41392-021-00544-0"}],"container-title":["The Journal of Pathology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.70094","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/path.70094","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/path.70094","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T14:32:28Z","timestamp":1789482748000},"score":1,"resource":{"primary":{"URL":"https:\/\/pathsocjournals.onlinelibrary.wiley.com\/doi\/10.1002\/path.70094"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,21]]},"references-count":56,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,10]]}},"alternative-id":["10.1002\/path.70094"],"URL":"https:\/\/doi.org\/10.1002\/path.70094","archive":["Portico"],"relation":{},"ISSN":["0022-3417","1096-9896"],"issn-type":[{"value":"0022-3417","type":"print"},{"value":"1096-9896","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,21]]},"assertion":[{"value":"2025-10-12","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-06-07","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-07-21","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}