Remodelling of the skin stromal niche during melanoma transformation

Remodelling of the skin stromal niche during melanoma transformation | 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 Remodelling of the skin stromal niche during melanoma transformation Göran Jönsson, Jacob Karlström, Teo Helkkula, Charlotta Hedner, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9292915/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 Skin melanocytes are repeatedly exposed to ultraviolet (UV) radiation making them susceptible to somatic mutations1. Thus 80% of benign melanocytic nevi have somatic mutations in the MAPK pathway genes most commonly affecting the BRAF and NRAS oncogenes 1,2. However, far from all benign nevi transforms into an invasive melanoma. Interaction between mutant melanocytes and their skin microenvironment presumably play a key role in cancer susceptibility. Here we show that the skin microenvironmental niche is remodelled at the most incipient stage of melanoma transformation. Analysis at single cell resolution of unique tissue biopsies from patients with clinically equivocal cutaneous melanocytic lesions were included. The main variation of the global transcriptional space across a high number of melanocytic lesions representing the full clinical spectrum defined an immune response signature that was significantly correlated with the number of chromosomal alterations and histopathological diagnosis. Single cell RNA sequencing analysis revealed that in particular interferon alpha (IFN-A) signalling was altered in multiple cell types already at the intermediate stage of melanocytic transformation. Keratinocytes in close proximity to highly atypical melanocytes had an inflamed phenotype expressing IFN-inducing genes as well as S100A8/9 and communicated with and recruited macrophages and T cells. Stimulated fibroblasts localized beneath the atypical melanocytic cells were marked by tenascin-c expression, and in invasive melanomas such fibroblasts formed an immunosuppressive cellular niche spatially located as a layer between activated lymphocytes and the melanoma cells. We propose a model where the skin microenvironment is remodelled early in melanoma transformation and is crucial for melanomas to persist and progress towards advanced stage. Health sciences/Pathogenesis Biological sciences/Cancer/Cancer microenvironment Full Text Additional Declarations There is NO Competing Interest. Supplementary Files ExtendedDataFigures.pdf Extended Data Figures 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. 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-9292915","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":622980896,"identity":"f4d68a9a-1a15-4e3e-948a-fae78da06711","order_by":0,"name":"Göran Jönsson","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCklEQVRIiWNgGAWjYPCCAwyMDRCWHBAbMDwgRYsxWEsCMVpgILGBkBZ5996HnwsY7jAwt/ce/vij4k762vbmDQyJbQz2/Di0GJ45biw9g+EZA2PPuTRpnjPPcredOVYA0pI4swGHlhlpDNI8DIcZGGfkmDEzth3O3XYjxwCkJcHgAE4tzL+hWow//mw7nG52/w1Yi709Di3yEmlsMFsMJHjbDieY3eABa2HcgMMvBjzH2Kx5GJ7xMPacMQP65bDhtjNpBQcSzkkkzsBlS3sb820ehjtyhu09xsAQOyxvdvzwxgcfymzs+XF4H+xHxn8MPIbICoCCEjicBbQFplIep5JRMApGwSgY8QAAyW1bIudygDoAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0001-6865-0147","institution":"Lund University","correspondingAuthor":true,"prefix":"","firstName":"Göran","middleName":"","lastName":"Jönsson","suffix":""},{"id":622980897,"identity":"41bbc639-7693-411e-8664-7988f0e9fbd2","order_by":1,"name":"Jacob Karlström","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Jacob","middleName":"","lastName":"Karlström","suffix":""},{"id":622980898,"identity":"1e7c0b9d-d542-4b3c-b04f-19a13b89220d","order_by":2,"name":"Teo Helkkula","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Teo","middleName":"","lastName":"Helkkula","suffix":""},{"id":622980899,"identity":"6a197929-5e72-4343-965d-049bc3293bbf","order_by":3,"name":"Charlotta Hedner","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Charlotta","middleName":"","lastName":"Hedner","suffix":""},{"id":622980900,"identity":"c8822cde-9a09-45b6-bd03-c1905b0e9a4c","order_by":4,"name":"Martin Lauss","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Martin","middleName":"","lastName":"Lauss","suffix":""},{"id":622980901,"identity":"2c761ab4-4ba9-4401-8097-191288188c9a","order_by":5,"name":"Katja Harbst","email":"","orcid":"https://orcid.org/0000-0002-8225-1510","institution":"Lund University Cancer Center, Lund","correspondingAuthor":false,"prefix":"","firstName":"Katja","middleName":"","lastName":"Harbst","suffix":""},{"id":622980902,"identity":"2f63fcf4-a1dc-4e1e-8566-67dbcfe5848c","order_by":6,"name":"Kamila Kaminska","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Kamila","middleName":"","lastName":"Kaminska","suffix":""},{"id":622980903,"identity":"552d793b-b329-43b5-9bf6-af8ed62463af","order_by":7,"name":"Florian Jeanneret","email":"","orcid":"https://orcid.org/0000-0002-9301-4019","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Florian","middleName":"","lastName":"Jeanneret","suffix":""},{"id":622980904,"identity":"d89ee2d1-e4a3-4181-8a58-b80321046797","order_by":8,"name":"Bengt Phung","email":"","orcid":"","institution":"Lund University Cancer Center, Lund","correspondingAuthor":false,"prefix":"","firstName":"Bengt","middleName":"","lastName":"Phung","suffix":""},{"id":622980905,"identity":"29879e44-8de3-4b07-8c3f-42fc1aa72134","order_by":9,"name":"Anna Hafström","email":"","orcid":"","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Hafström","suffix":""},{"id":622980906,"identity":"2605c228-931e-4842-a280-cf2e53004e07","order_by":10,"name":"Ana Carneiro","email":"","orcid":"","institution":"Lund University Cancer Center, Lund","correspondingAuthor":false,"prefix":"","firstName":"Ana","middleName":"","lastName":"Carneiro","suffix":""},{"id":622980907,"identity":"97c22505-fc53-45d8-973f-f9e4987b8a98","order_by":11,"name":"Kristian Pietras","email":"","orcid":"https://orcid.org/0000-0001-6738-4705","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Kristian","middleName":"","lastName":"Pietras","suffix":""},{"id":622980908,"identity":"e754e140-5156-423b-8693-bceb3d9ed7cb","order_by":12,"name":"Karolin Isaksson","email":"","orcid":"","institution":"Lund University Cancer Center, Lund","correspondingAuthor":false,"prefix":"","firstName":"Karolin","middleName":"","lastName":"Isaksson","suffix":""},{"id":622980909,"identity":"9c7888dc-2998-4587-b664-c6c5c561d306","order_by":13,"name":"Kari Nielsen","email":"","orcid":"https://orcid.org/0000-0002-7363-0455","institution":"Lund University Cancer Center, Lund","correspondingAuthor":false,"prefix":"","firstName":"Kari","middleName":"","lastName":"Nielsen","suffix":""},{"id":622980910,"identity":"ea5d8c68-5bf8-4152-95a0-181ad093f729","order_by":14,"name":"Jonas Sjölund","email":"","orcid":"https://orcid.org/0000-0002-6992-3415","institution":"Lund University","correspondingAuthor":false,"prefix":"","firstName":"Jonas","middleName":"","lastName":"Sjölund","suffix":""}],"badges":[],"createdAt":"2026-04-01 13:58:27","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9292915/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9292915/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107481258,"identity":"3f9a19b4-c552-40d9-a572-bee9baeb55a3","added_by":"auto","created_at":"2026-04-22 02:16:45","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":36478924,"visible":true,"origin":"","legend":"Article File","description":"","filename":"ManuscriptKarlstromc.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9292915/v1_covered_53553f49-e8c4-451e-af6f-1d449cf2d627.pdf"},{"id":107030826,"identity":"f8458580-2525-410b-91a0-f404d57f0e48","added_by":"auto","created_at":"2026-04-16 02:55:33","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15726619,"visible":true,"origin":"","legend":"Extended Data Figures","description":"","filename":"ExtendedDataFigures.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9292915/v1/6b1bb6e3d120db87d81b3f81.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Remodelling of the skin stromal niche during melanoma transformation","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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 Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-9292915/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9292915/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Skin melanocytes are repeatedly exposed to ultraviolet (UV) radiation making them susceptible to somatic mutations1. Thus 80% of benign melanocytic nevi have somatic mutations in the MAPK pathway genes most commonly affecting the BRAF and NRAS oncogenes 1,2. However, far from all benign nevi transforms into an invasive melanoma. Interaction between mutant melanocytes and their skin microenvironment presumably play a key role in cancer susceptibility. Here we show that the skin microenvironmental niche is remodelled at the most incipient stage of melanoma transformation. Analysis at single cell resolution of unique tissue biopsies from patients with clinically equivocal cutaneous melanocytic lesions were included. The main variation of the global transcriptional space across a high number of melanocytic lesions representing the full clinical spectrum defined an immune response signature that was significantly correlated with the number of chromosomal alterations and histopathological diagnosis. Single cell RNA sequencing analysis revealed that in particular interferon alpha (IFN-A) signalling was altered in multiple cell types already at the intermediate stage of melanocytic transformation. Keratinocytes in close proximity to highly atypical melanocytes had an inflamed phenotype expressing IFN-inducing genes as well as S100A8/9 and communicated with and recruited macrophages and T cells. Stimulated fibroblasts localized beneath the atypical melanocytic cells were marked by tenascin-c expression, and in invasive melanomas such fibroblasts formed an immunosuppressive cellular niche spatially located as a layer between activated lymphocytes and the melanoma cells. We propose a model where the skin microenvironment is remodelled early in melanoma transformation and is crucial for melanomas to persist and progress towards advanced stage.","manuscriptTitle":"Remodelling of the skin stromal niche during melanoma transformation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-16 02:54:34","doi":"10.21203/rs.3.rs-9292915/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-cancer","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"natcancer","sideBox":"Learn more about [Nature Cancer](http://www.nature.com/natcancer/)","snPcode":"","submissionUrl":"","title":"Nature Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"4bafea59-f307-4848-aaf5-ae6131b1ddd7","owner":[],"postedDate":"April 16th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":66297129,"name":"Health sciences/Pathogenesis"},{"id":66297130,"name":"Biological sciences/Cancer/Cancer microenvironment"}],"tags":[],"updatedAt":"2026-04-16T02:54:34+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-16 02:54:34","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9292915","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9292915","identity":"rs-9292915","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}