A Reduced-Order Model of IL-6 Signaling Reveals Determinants of Phenotypic Heterogeneity in Prostate Cancer Cells

A Reduced-Order Model of IL-6 Signaling Reveals Determinants of Phenotypic Heterogeneity in Prostate Cancer Cells | 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 A Reduced-Order Model of IL-6 Signaling Reveals Determinants of Phenotypic Heterogeneity in Prostate Cancer Cells Mahule Roy, Subhas Roy This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7933651/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 Interleukin-6 (IL-6) drives paradoxical phenotypic outcomes in androgen-sensitive LNCaP prostate cancer cells—ranging from proliferation to G1 growth arrest—despite uniform extracellular stimulation. This non-genetic heterogeneity arises from cell-tocell variability in signaling protein abundances and regulatory dynamics. To dissect this phenomenon, we developed a reduced-order, biologically grounded ordinary differential equation (ODE) model of IL-6 signaling that integrates JAK/STAT3 and MAPK cascades, delayed SOCS3-mediated negative feedback, and downstream cell-cycle effectors (p21 kip1 , c-Myc, cyclin E/CDK2). Through systematic parameter sweeps, Monte Carlo simulations, local sensitivity analysis, and targeted perturbations mimicking knockdown/ overexpression, we demonstrate that heterogeneity in total receptor expression (R total ), STAT3 abundance, and SOCS3 transcriptional delay are sufficient to drive bifurcations in cell fate. Our model predicts that high receptor/STAT3 levels favor growth arrest due to amplified SOCS3 feedback, while delayed feedback permits transient proliferation. Local sensitivity analysis identifies p21 synthesis and degradation as the most influential parameters. A heatmap of phenotypic score difference across Rtotal–STAT total space reveals a sharp transition boundary, offering testable hypotheses for single-cell experiments. These findings underscore the role of dynamic feedback architecture— not just genetic variation—in generating phenotypic diversity and suggest novel therapeutic strategies targeting cell-cycle regulators downstream of IL-6. Systems Biology Systems Biology Reduced-Order Modeling Prostate Cancer Non-genetic Heterogeneity Full Text Additional Declarations The authors declare no competing interests. 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. 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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-7933651","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":534059752,"identity":"d8330336-78f9-4466-b46e-5572b824d6f5","order_by":0,"name":"Mahule Roy","email":"","orcid":"https://orcid.org/0009-0005-7259-771X","institution":"University of Oxford","correspondingAuthor":false,"prefix":"","firstName":"Mahule","middleName":"","lastName":"Roy","suffix":""},{"id":534059753,"identity":"3384ec30-e3f3-45fd-84e2-266163f265c4","order_by":1,"name":"Subhas Roy","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA7UlEQVRIiWNgGAWjYLACxoYDDAzszQcfANk8fMRr4TmWbADSwka8FgkfMwkQh6AW8/Ye48+8O+7Iy8/gMav8mmMnw8bA/PDRDTxaZM6cMZPmPfPMcMPttrLbstuSgQ5jMzbOwaNFQiLHjJm37TDjBpnD225LbmMGauFhkyagBeiwtsP282ckmBVLbqsnSouBNFBLYsONFDPGj9sOE6GF51iZ5Nwzh5M3nDmWLM247TgPGzMhv7A3b/7wdsdh2/ntzQc//txWbc/P3vzwMT4tDAwcBnAmMw+YxKscBNgfwJmMPwiqHgWjYBSMgpEIAOXsSoPJQrHAAAAAAElFTkSuQmCC","orcid":"","institution":"TATA Conusmer Products Limited","correspondingAuthor":true,"prefix":"","firstName":"Subhas","middleName":"","lastName":"Roy","suffix":""}],"badges":[],"createdAt":"2025-10-23 15:33:22","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7933651/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7933651/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":94245822,"identity":"9e99b5cf-0cbb-42f0-a081-c74b57c8a6cc","added_by":"auto","created_at":"2025-10-24 05:28:57","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":942374,"visible":true,"origin":"","legend":"","description":"","filename":"ComputationalModelling.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7933651/v1_covered_5ddc6404-f766-41cd-a10d-334414402a09.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eA Reduced-Order Model of IL-6 Signaling Reveals Determinants of Phenotypic Heterogeneity in Prostate Cancer Cells\u003c/p\u003e","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"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":"Systems Biology, Reduced-Order Modeling, Prostate Cancer, Non-genetic Heterogeneity","lastPublishedDoi":"10.21203/rs.3.rs-7933651/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7933651/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eInterleukin-6 (IL-6) drives paradoxical phenotypic outcomes in androgen-sensitive LNCaP prostate cancer cells—ranging from proliferation to G1 growth arrest—despite uniform extracellular stimulation. This non-genetic heterogeneity arises from cell-tocell variability in signaling protein abundances and regulatory dynamics. To dissect this phenomenon, we developed a reduced-order, biologically grounded ordinary differential equation (ODE) model of IL-6 signaling that integrates JAK/STAT3 and MAPK cascades, delayed SOCS3-mediated negative feedback, and downstream cell-cycle effectors (p21\u003csup\u003ekip1\u003c/sup\u003e, c-Myc, cyclin E/CDK2). Through systematic parameter sweeps, Monte Carlo simulations, local sensitivity analysis, and targeted perturbations mimicking knockdown/ overexpression, we demonstrate that heterogeneity in total receptor expression (R\u003csub\u003etotal\u003c/sub\u003e), STAT3 abundance, and SOCS3 transcriptional delay are sufficient to drive bifurcations in cell fate. Our model predicts that high receptor/STAT3 levels favor growth arrest due to amplified SOCS3 feedback, while delayed feedback permits transient proliferation. Local sensitivity analysis identifies p21 synthesis and degradation as the most influential parameters. A heatmap of phenotypic score difference across Rtotal–STAT\u003csub\u003etotal\u003c/sub\u003e space reveals a sharp transition boundary, offering testable hypotheses for single-cell experiments. 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