LAMA3 Orchestrates Immune Evasion and Metabolic Reprogramming in Pancreatic Ductal Adenocarcinoma: Insights from Multi-Omics Integration

LAMA3 Orchestrates Immune Evasion and Metabolic Reprogramming in Pancreatic Ductal Adenocarcinoma: Insights from Multi-Omics Integration | 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 Research Article LAMA3 Orchestrates Immune Evasion and Metabolic Reprogramming in Pancreatic Ductal Adenocarcinoma: Insights from Multi-Omics Integration Ruixiang li, Yuheng Gu, Hua Yang, Shangke Huang This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7635163/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 13 You are reading this latest preprint version Abstract Background Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterized by immune evasion and metabolic reprogramming. The role of laminin subunit alpha 3 (LAMA3), a key component in adhesion and signaling, remains poorly defined in PDAC. Methods We performed an integrative multi-omics analysis combining bulk and single-cell transcriptomics, WGCNA, CNV inference, pseudotime trajectory, enrichment analysis, and regulatory network modeling. Results LAMA3 was markedly upregulated in PDAC and enriched in pathways related to adhesion, extracellular matrix remodeling, and immune regulation. High LAMA3 expression correlated positively with immunosuppressive macrophages but negatively with CD8⁺ T-cell infiltration. Single-cell analysis revealed predominant epithelial expression, high CNV activity, and progressive upregulation along pseudotime, implicating a role in tumor evolution. Functional enrichment linked LAMA3 to cell cycle regulation, p53 signaling, and metabolic reprogramming. Regulatory modeling identified EP300 as an upstream transcriptional regulator, while molecular docking suggested indirect pharmacological targeting through Prostaglandin J2. Conclusion Our findings highlight LAMA3 as a central regulator of adhesion, immune evasion, and tumor progression in PDAC, supporting its potential as a diagnostic biomarker and therapeutic target. PDAC LAMA3 immune microenvironment EP300 regulatory network Prostaglandin J2 Full Text Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 03 Nov, 2025 Reviews received at journal 28 Oct, 2025 Reviewers agreed at journal 23 Oct, 2025 Reviews received at journal 18 Oct, 2025 Reviews received at journal 13 Oct, 2025 Reviewers agreed at journal 10 Oct, 2025 Reviewers agreed at journal 09 Oct, 2025 Reviewers agreed at journal 29 Sep, 2025 Reviewers agreed at journal 28 Sep, 2025 Reviewers invited by journal 28 Sep, 2025 Editor assigned by journal 17 Sep, 2025 Submission checks completed at journal 17 Sep, 2025 First submitted to journal 16 Sep, 2025 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. 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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-7635163","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":526545225,"identity":"c79e5e71-6bf8-44ce-9d7a-c3fef548f949","order_by":0,"name":"Ruixiang li","email":"","orcid":"","institution":"Southwest Medical University","correspondingAuthor":false,"prefix":"","firstName":"Ruixiang","middleName":"","lastName":"li","suffix":""},{"id":526545226,"identity":"5a0ea756-a1ec-400f-8f11-54d7019db049","order_by":1,"name":"Yuheng Gu","email":"","orcid":"","institution":"Southwest Medical 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Integration","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"discover-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dion","sideBox":"Learn more about [Discover Oncology](https://www.springer.com/12672)","snPcode":"","submissionUrl":"","title":"Discover Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"PDAC, LAMA3, immune microenvironment, EP300, regulatory network, Prostaglandin J2","lastPublishedDoi":"10.21203/rs.3.rs-7635163/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7635163/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003ePancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterized by immune evasion and metabolic reprogramming. The role of laminin subunit alpha 3 (LAMA3), a key component in adhesion and signaling, remains poorly defined in PDAC.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe performed an integrative multi-omics analysis combining bulk and single-cell transcriptomics, WGCNA, CNV inference, pseudotime trajectory, enrichment analysis, and regulatory network modeling.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eLAMA3 was markedly upregulated in PDAC and enriched in pathways related to adhesion, extracellular matrix remodeling, and immune regulation. High LAMA3 expression correlated positively with immunosuppressive macrophages but negatively with CD8⁺ T-cell infiltration. Single-cell analysis revealed predominant epithelial expression, high CNV activity, and progressive upregulation along pseudotime, implicating a role in tumor evolution. Functional enrichment linked LAMA3 to cell cycle regulation, p53 signaling, and metabolic reprogramming. Regulatory modeling identified EP300 as an upstream transcriptional regulator, while molecular docking suggested indirect pharmacological targeting through Prostaglandin J2.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eOur findings highlight LAMA3 as a central regulator of adhesion, immune evasion, and tumor progression in PDAC, supporting its potential as a diagnostic biomarker and therapeutic target.\u003c/p\u003e","manuscriptTitle":"LAMA3 Orchestrates Immune Evasion and Metabolic Reprogramming in Pancreatic Ductal Adenocarcinoma: Insights from Multi-Omics Integration","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-09 17:37:21","doi":"10.21203/rs.3.rs-7635163/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-11-03T15:33:34+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-28T09:13:28+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"316380246328382205904991194301621362524","date":"2025-10-23T08:31:12+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-19T02:01:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-10-13T22:30:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"267294840733427384786718780013540887647","date":"2025-10-10T08:15:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"78647163512555510462538328611772157359","date":"2025-10-09T04:35:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"145062762223441528139805755022604462632","date":"2025-09-29T19:30:42+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"63543972274821284027474383383681945038","date":"2025-09-29T02:37:37+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-28T13:07:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-17T06:58:04+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-09-17T06:57:56+00:00","index":"","fulltext":""},{"type":"submitted","content":"Discover Oncology","date":"2025-09-17T03:11:38+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"discover-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"dion","sideBox":"Learn more about [Discover Oncology](https://www.springer.com/12672)","snPcode":"","submissionUrl":"","title":"Discover Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Discover Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"15c344f2-8bef-4105-8369-4b5147013b13","owner":[],"postedDate":"October 9th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-03-04T10:25:18+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-09 17:37:21","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7635163","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7635163","identity":"rs-7635163","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}