Proteomic and phospho-proteomic longitudinal signatures of human skeletal muscle in lung cancer cachexia

Proteomic and phospho-proteomic longitudinal signatures of human skeletal muscle in lung cancer cachexia | 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 Proteomic and phospho-proteomic longitudinal signatures of human skeletal muscle in lung cancer cachexia Lykke Sylow, Jonas Sørensen, Christian Voldstedlund, Edmund Battey, and 10 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8251297/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 Weight loss is a potentially deadly hallmark of many cancers, including lung cancer. In particular, the loss of skeletal muscle mass and function impairs survival and lowers quality of life. Despite being a major determinant of prognosis, the molecular drivers of muscle wasting remain ill-defined. Therefore, there is a critical need for human molecular data to support the development of effective therapies for this currently untreatable condition. Here, we utilize cutting-edge proteomics technology to longitudinally map the proteome and phosphoproteome of skeletal muscle from patients with newly diagnosed, advanced-stage non-small cell lung cancer during their treatment. Leveraging deep in vivo clinical phenotyping of activity, body composition, muscle quality, and nutritional risk, we identified 118/174 muscle proteins/phospho-sites associated with cachexia at diagnosis with indications of sexual dimorphism. Treatment altered 278 proteins and 1,155 phospho-sites, of which 137/91 proteins/phospho-sites were associated with muscle wasting. Our findings highlight disrupted calcium, anabolic, and stress signalling, alongside extracellular matrix and mitochondrial alterations, as key molecular features of cachexia in non-small cell lung cancer. These clinically anchored proteomic and phosphoproteomic signatures provide potential targets for future research. Biological sciences/Cancer/Lung cancer/Non-small-cell lung cancer Biological sciences/Cell biology/Mechanisms of disease Biological sciences/Molecular biology/Proteomics/Protein–protein interaction networks Full Text Additional Declarations Yes there is potential Competing Interest. Seppo W. Langer: Research collaboration, speaker fee and advisory board honorarium: Amgen, Roche, Pfizer, Johnson and Johnson, Bristol Myers Squibb, Ipsen, Boehringer Ingelheim, Daiichi Dankyo. 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-8251297","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":563056619,"identity":"e8e42885-249c-4c5a-9f33-bf74ade4b489","order_by":0,"name":"Lykke Sylow","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYBACAwY2ZhAtw8DAfABIMzNIAEnJBiK08DAwsCWQrIXHgEgtEmnJBh/+HObhl8j5/Jl3hzWD5IwExpsz8Gs5nDiz7TCP5IzcbdK8Z9IZpCUSmC034NWS3nyYt+Ewj8Ht3G3MvG2HGeQkEtgkHxDS8ucPSEvO489Eakk7nMzABtbCIA3SIg3SgtdhPM+SDXvb0nkk5z8zk5wLYvQ8bLbE53379jRjiR9/rOX4eQ4//vC2zVpO4njywZs9eLQwCCSAyGY4HxhBjA34NDAw8B8AkXX4FY2CUTAKRsHIBgDqmEkqQky2hQAAAABJRU5ErkJggg==","orcid":"","institution":"University of Copenhagen","correspondingAuthor":true,"prefix":"","firstName":"Lykke","middleName":"","lastName":"Sylow","suffix":""},{"id":563056620,"identity":"3ddc7573-307a-4133-b029-7a6a7f61f039","order_by":1,"name":"Jonas Sørensen","email":"","orcid":"https://orcid.org/0000-0002-2055-0953","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Jonas","middleName":"","lastName":"Sørensen","suffix":""},{"id":563056621,"identity":"0e12b87e-fb14-4457-a923-fb08a4e0094b","order_by":2,"name":"Christian Voldstedlund","email":"","orcid":"https://orcid.org/0000-0002-6368-8995","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Voldstedlund","suffix":""},{"id":563056622,"identity":"f0243ea1-fdad-459a-b774-b72d3fb7b856","order_by":3,"name":"Edmund Battey","email":"","orcid":"https://orcid.org/0000-0003-4465-7533","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Edmund","middleName":"","lastName":"Battey","suffix":""},{"id":563056623,"identity":"5093bb28-6154-482a-8724-35035d34afe9","order_by":4,"name":"Zakarias Ogueboule","email":"","orcid":"https://orcid.org/0000-0002-3233-7340","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Zakarias","middleName":"","lastName":"Ogueboule","suffix":""},{"id":563056624,"identity":"6421c541-acd0-4d3d-ba95-55e5f9b4c6d5","order_by":5,"name":"Andrea Irazoki","email":"","orcid":"","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Andrea","middleName":"","lastName":"Irazoki","suffix":""},{"id":563056625,"identity":"e18d6214-1f08-4f1a-85fa-a24cdbde756f","order_by":6,"name":"Johanne Modvig","email":"","orcid":"https://orcid.org/0009-0008-8957-4698","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Johanne","middleName":"","lastName":"Modvig","suffix":""},{"id":563056626,"identity":"6f41d90a-57ce-4302-b7b1-46133461c9f7","order_by":7,"name":"Cathrine Knøs","email":"","orcid":"","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Cathrine","middleName":"","lastName":"Knøs","suffix":""},{"id":563056627,"identity":"0e745235-662b-4baf-a66d-e309c488af33","order_by":8,"name":"Anna Hammershøi","email":"","orcid":"","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Anna","middleName":"","lastName":"Hammershøi","suffix":""},{"id":563056628,"identity":"c8b58fc0-28b8-47c5-b3f5-207663c11abc","order_by":9,"name":"Christian Carl","email":"","orcid":"","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Carl","suffix":""},{"id":563056629,"identity":"a6bea4e9-f026-4f9a-ad09-4aae057d7f20","order_by":10,"name":"Steffen Raun","email":"","orcid":"","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Steffen","middleName":"","lastName":"Raun","suffix":""},{"id":563056630,"identity":"1be6666f-be3a-46bb-8818-ac7c770ff388","order_by":11,"name":"Oksana Dmytriyeva","email":"","orcid":"","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Oksana","middleName":"","lastName":"Dmytriyeva","suffix":""},{"id":563056631,"identity":"0149cea8-44ef-4b65-8fda-1f81cfaf8b67","order_by":12,"name":"Erik Richter","email":"","orcid":"https://orcid.org/0000-0002-6850-3056","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Erik","middleName":"","lastName":"Richter","suffix":""},{"id":563056632,"identity":"9c62bcfe-7ada-46f1-a9b6-7f59c49eaae3","order_by":13,"name":"Seppo Langer","email":"","orcid":"","institution":"University of Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Seppo","middleName":"","lastName":"Langer","suffix":""}],"badges":[],"createdAt":"2025-12-01 14:16:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8251297/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8251297/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103376884,"identity":"db8dee77-c34c-457d-9190-c0b2c2459359","added_by":"auto","created_at":"2026-02-25 04:10:25","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":6521550,"visible":true,"origin":"","legend":"Article File","description":"","filename":"SorensenVoldstedlundetalNatMed.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8251297/v1_covered_35f80a03-ba89-4cb1-8286-263576e4c1bc.pdf"}],"financialInterests":"\u003cb\u003eYes\u003c/b\u003e there is potential Competing Interest.\nSeppo W. Langer: Research collaboration, speaker fee and advisory board honorarium: Amgen, Roche, Pfizer, Johnson and Johnson, Bristol Myers Squibb, Ipsen, Boehringer Ingelheim, Daiichi Dankyo.","formattedTitle":"Proteomic and phospho-proteomic longitudinal signatures of human skeletal muscle in lung cancer cachexia","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-8251297/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8251297/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Weight loss is a potentially deadly hallmark of many cancers, including lung cancer. In particular, the loss of skeletal muscle mass and function impairs survival and lowers quality of life. Despite being a major determinant of prognosis, the molecular drivers of muscle wasting remain ill-defined. Therefore, there is a critical need for human molecular data to support the development of effective therapies for this currently untreatable condition. Here, we utilize cutting-edge proteomics technology to longitudinally map the proteome and phosphoproteome of skeletal muscle from patients with newly diagnosed, advanced-stage non-small cell lung cancer during their treatment. Leveraging deep in vivo clinical phenotyping of activity, body composition, muscle quality, and nutritional risk, we identified 118/174 muscle proteins/phospho-sites associated with cachexia at diagnosis with indications of sexual dimorphism. Treatment altered 278 proteins and 1,155 phospho-sites, of which 137/91 proteins/phospho-sites were associated with muscle wasting. Our findings highlight disrupted calcium, anabolic, and stress signalling, alongside extracellular matrix and mitochondrial alterations, as key molecular features of cachexia in non-small cell lung cancer. These clinically anchored proteomic and phosphoproteomic signatures provide potential targets for future research.","manuscriptTitle":"Proteomic and phospho-proteomic longitudinal signatures of human skeletal muscle in lung cancer cachexia","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-25 04:09:48","doi":"10.21203/rs.3.rs-8251297/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"e6d6e2e8-1503-4381-a45b-62afb30709a8","owner":[],"postedDate":"February 25th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":59963205,"name":"Biological sciences/Cancer/Lung cancer/Non-small-cell lung cancer"},{"id":59963206,"name":"Biological sciences/Cell biology/Mechanisms of disease"},{"id":59963207,"name":"Biological sciences/Molecular biology/Proteomics/Protein\u0026#x2013;protein interaction networks"}],"tags":[],"updatedAt":"2026-02-25T04:09:48+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-25 04:09:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8251297","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8251297","identity":"rs-8251297","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}