Neuromedin U promotes lung adenocarcinoma progression by enhancing nucleotide metabolism and potentiating fibrosis in the tumor microenvironment

Neuromedin U promotes lung adenocarcinoma progression by enhancing nucleotide metabolism and potentiating fibrosis in the tumor microenvironment | 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 Neuromedin U promotes lung adenocarcinoma progression by enhancing nucleotide metabolism and potentiating fibrosis in the tumor microenvironment Shih Sheng Jiang, Shih-Miao Li, Chi-Shuan Fan, Tzu-Yu Chen, Wen-Tsen Fang, and 14 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8171505/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality, with limited treatment options for EGFR-wild-type patients and persistent intrinsic resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in some EGFR-mutated cases. Neuromedin U (NMU), which encodes a neuropeptide previously associated with poor prognosis, has emerged as a candidate gene linked to reduced EGFR-TKI efficacy. Here, we identify NMU as a multifaceted effector of LUAD progression. Transcriptomic analyses across LUAD cohorts revealed that NMU expression correlates with poor survival and enrichment of purine metabolism signatures. Mechanistically, NMU upregulates key purine biosynthesis genes, including IMPDH1 , GMPS , and RRM1 , in a NTSR1-dependent manner. Targeted metabolomic profiling and 15 N-glutamine isotope tracing confirmed that NMU enhances IMPDH1-mediated guanine nucleotide synthesis, supporting increased proliferative capacity. Pharmacologic inhibition of NMU signaling or IMPDH1 suppressed LUAD cell viability and AKT signaling, with guanosine supplementation partially rescuing these effects, functionally validating the NMU-IMPDH1 axis. Concurrently, NMU expression was associated with elevated levels of fibrosis-related markers including COL1A1 , FN1 , and ACTA2 , alongside transcriptomic and histological features of extracellular matrix remodeling and stromal expansion. These findings, supported by co-culture assays and in vivo models, suggest that NMU may influence stromal remodeling, possibly via TGF-β signaling. Notably, in vivo NMU inhibition reduced both tumor growth and fibrotic features, and combination therapy with SR48692 (NTSR1 inhibitor) and osimertinib yielded superior therapeutic efficacy. Together, these results identify NMU as a key mediator of LUAD progression through both tumor-intrinsic metabolic reprogramming and stromal remodeling pathways. Targeting the NMU-IMPDH1 axis may offer a novel strategy to suppress tumor proliferation and reshape the tumor microenvironment in LUAD patients with high NMU expressing tumors. Biological sciences/Cancer/Lung cancer/Non-small-cell lung cancer Biological sciences/Cancer/Cancer metabolism Biological sciences/Cancer/Cancer microenvironment Biological sciences/Cancer/Cancer therapy/Cancer therapeutic resistance Biological sciences/Cancer/Tumour biomarkers Full Text Additional Declarations (Not answered) Supplementary Files CCDSupplementaryfile2originalimagesWBimages.pdf Supplementary Information 2 CDDsupplementaryfile.pdf Supplementary Information Cite Share Download PDF Status: Posted 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. 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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-8171505","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":554546891,"identity":"f2d0cec4-dfa8-4f2e-94c6-56054cea266a","order_by":0,"name":"Shih Sheng 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microenvironment","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"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":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8171505/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8171505/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Lung adenocarcinoma (LUAD) remains a leading cause of cancer mortality, with limited treatment options for EGFR-wild-type patients and persistent intrinsic resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in some EGFR-mutated cases. Neuromedin U (NMU), which encodes a neuropeptide previously associated with poor prognosis, has emerged as a candidate gene linked to reduced EGFR-TKI efficacy. Here, we identify NMU as a multifaceted effector of LUAD progression. Transcriptomic analyses across LUAD cohorts revealed that NMU expression correlates with poor survival and enrichment of purine metabolism signatures. Mechanistically, NMU upregulates key purine biosynthesis genes, including \u003ci\u003eIMPDH1\u003c/i\u003e, \u003ci\u003eGMPS\u003c/i\u003e, and \u003ci\u003eRRM1\u003c/i\u003e, in a NTSR1-dependent manner. Targeted metabolomic profiling and \u003csup\u003e15\u003c/sup\u003eN-glutamine isotope tracing confirmed that NMU enhances IMPDH1-mediated guanine nucleotide synthesis, supporting increased proliferative capacity. Pharmacologic inhibition of NMU signaling or IMPDH1 suppressed LUAD cell viability and AKT signaling, with guanosine supplementation partially rescuing these effects, functionally validating the NMU-IMPDH1 axis. Concurrently, \u003ci\u003eNMU\u003c/i\u003e expression was associated with elevated levels of fibrosis-related markers including \u003ci\u003eCOL1A1\u003c/i\u003e, \u003ci\u003eFN1\u003c/i\u003e, and \u003ci\u003eACTA2\u003c/i\u003e, alongside transcriptomic and histological features of extracellular matrix remodeling and stromal expansion. These findings, supported by co-culture assays and \u003ci\u003ein vivo\u003c/i\u003e models, suggest that NMU may influence stromal remodeling, possibly via TGF-β signaling. Notably, \u003ci\u003ein vivo\u003c/i\u003e NMU inhibition reduced both tumor growth and fibrotic features, and combination therapy with SR48692 (NTSR1 inhibitor) and osimertinib yielded superior therapeutic efficacy. Together, these results identify NMU as a key mediator of LUAD progression through both tumor-intrinsic metabolic reprogramming and stromal remodeling pathways. Targeting the NMU-IMPDH1 axis may offer a novel strategy to suppress tumor proliferation and reshape the tumor microenvironment in LUAD patients with high NMU expressing tumors.","manuscriptTitle":"Neuromedin U promotes lung adenocarcinoma progression by enhancing nucleotide metabolism and potentiating fibrosis in the tumor microenvironment","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-05 05:11:30","doi":"10.21203/rs.3.rs-8171505/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b94cb4fb-7e20-4c87-b42e-30fa0c896570","owner":[],"postedDate":"December 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":59010059,"name":"Biological sciences/Cancer/Lung cancer/Non-small-cell lung cancer"},{"id":59010060,"name":"Biological sciences/Cancer/Cancer metabolism"},{"id":59010061,"name":"Biological sciences/Cancer/Cancer microenvironment"},{"id":59010062,"name":"Biological sciences/Cancer/Cancer therapy/Cancer therapeutic resistance"},{"id":59010063,"name":"Biological sciences/Cancer/Tumour biomarkers"}],"tags":[],"updatedAt":"2026-01-29T11:16:35+00:00","versionOfRecord":[],"versionCreatedAt":"2025-12-05 05:11:30","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8171505","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8171505","identity":"rs-8171505","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}