Role of myeloid cells and leukotriene signalling in Uveal Melanoma progression

Role of myeloid cells and leukotriene signalling in Uveal Melanoma progression | 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 Role of myeloid cells and leukotriene signalling in Uveal Melanoma progression Marina Mione, Francesca Lorenzini, Vittorio Bontempi, Antonella Calore, and 12 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8735458/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract Uveal melanoma (UM) is the most common and fatal primary intraocular malignancy in adults. Most UM patients carry activating mutations in Gαq or Gα11, alpha subunits of trimeric G-proteins associated with cysteinyl leukotriene receptors (CYSLTRs). To investigate the involvement of leukotrienes in activating CYSLTRs and their ability to induce YAP signalling, we generated four genetically distinct zebrafish uveal melanoma models and analysed the role of different cells in leukotriene production. Treatment of primary UM cells and zebrafish UM explants with leukotrieneD4 (LTD4) induced the overexpression of PTK2/FAK, a positive activator of YAP signalling, and upregulation of YAP targets, while co-treatment with a CYSLTR2 inhibitor prevented LTD4-mediated YAP activation. Single-cell transcriptomic analysis of the zebrafish UM models revealed neutrophils as the major producers of leukotrienes and provided information on the YAP transcriptional program activated by leukotrienes. In support of the role of neutrophils in UM progression, we found that transplantation of UM cells in zebrafish induced reactive neutrophilia and neutrophil infiltration of the transplanted tumours, while neutrophil ablation reduces tumour growth. We suggest that neutrophils contribute to UM development by producing LTD4, which interacts with CYSLTR2 and facilitated by the activated status of mutant Gα11, promotes YAP signalling and UM progression. Biological sciences/Cancer/Cancer models Biological sciences/Cancer/Eye cancer Full Text Additional Declarations There is NO Competing Interest. Supplementary Files LorenzinietalSUPPFIGURESLEGENDS.pdf Supplementary figures Suppl.video1.mp4 Supplementary video 1 Suppl.video3.mp4 Supplementary video 3 Supplementarytable5numberofcancercellspersamplepercluster.xlsb Supplementary table 5 Suppl.video2.mp4 Supplementary video 2 Supplementarytable8DEYAPtargets1.xlsx Supplementary table 8 Supplementarytable1numberofcellsperclusterpersample.xlsx Supplementary table 1 Suppl.video4.mp4 Supplementary video 4 Supplementarytable2markerspercluster.xlsb Supplementary table 2 Supplementarytable9YAPtargets.xlsx Supplementary table 9 Supplementarytable4proportiontest.xlsx Supplementary table 4 Supplementarytable6markersperclustersamplepresto.xlsb Supplementary table 6 Supplementarytable7GSEAHallmarkcombined.xlsx Supplementary table 7 Supplementarytable10kmDE.xlsx Supplementary table 10 Suppl.video5.mp4 Supplementary video 5 Supplementarytable3numberofcellspercelltypepersample.xlsx Supplementary table 3 Cite Share Download PDF Status: Under Review 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. 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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-8735458","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":601354334,"identity":"a91866d3-6de4-4dca-83e3-88acbbcb133a","order_by":0,"name":"Marina 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progression","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature 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Most UM patients carry activating mutations in Gαq or Gα11, alpha subunits of trimeric G-proteins associated with cysteinyl leukotriene receptors (CYSLTRs). To investigate the involvement of leukotrienes in activating CYSLTRs and their ability to induce YAP signalling, we generated four genetically distinct zebrafish uveal melanoma models and analysed the role of different cells in leukotriene production.\r\nTreatment of primary UM cells and zebrafish UM explants with leukotrieneD4 (LTD4) induced the overexpression of PTK2/FAK, a positive activator of YAP signalling, and upregulation of YAP targets, while co-treatment with a CYSLTR2 inhibitor prevented LTD4-mediated YAP activation. Single-cell transcriptomic analysis of the zebrafish UM models revealed neutrophils as the major producers of leukotrienes and provided information on the YAP transcriptional program activated by leukotrienes. In support of the role of neutrophils in UM progression, we found that transplantation of UM cells in zebrafish induced reactive neutrophilia and neutrophil infiltration of the transplanted tumours, while neutrophil ablation reduces tumour growth.\r\nWe suggest that neutrophils contribute to UM development by producing LTD4, which interacts with CYSLTR2 and facilitated by the activated status of mutant Gα11, promotes YAP signalling and UM progression.","manuscriptTitle":"Role of myeloid cells and leukotriene signalling in Uveal Melanoma progression","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-03-11 13:00:34","doi":"10.21203/rs.3.rs-8735458/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-biology","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsbio","sideBox":"Learn more about [Communications Biology](http://www.nature.com/commsbio/)","snPcode":"","submissionUrl":"","title":"Communications Biology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"944cc7fc-c451-4247-8871-51e9ba3682e1","owner":[],"postedDate":"March 11th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":63998632,"name":"Biological sciences/Cancer/Cancer models"},{"id":63998633,"name":"Biological sciences/Cancer/Eye cancer"}],"tags":[],"updatedAt":"2026-04-24T10:56:47+00:00","versionOfRecord":[],"versionCreatedAt":"2026-03-11 13:00:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8735458","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8735458","identity":"rs-8735458","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}