Unraveling the YAP1-TGFb1 axis: a key driver of androgen receptor loss in prostate cancer-associated fibroblasts

Unraveling the YAP1-TGFb1 axis: a key driver of androgen receptor loss in prostate cancer-associated fibroblasts | 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 Unraveling the YAP1-TGFb1 axis: a key driver of androgen receptor loss in prostate cancer-associated fibroblasts Elena Brunner, Elisabeth Damisch, Melanie Emma Groninger, Lukas Nommensen, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3258823/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Due to their pivotal roles in tumor progression and therapy resistance, cancer-associated fibroblasts (CAF) are considered key therapeutic targets with loss of stromal androgen receptor (AR) a poorly understood hallmark of aggressive prostate cancer (PCa). A paucity of pre-clinical models however has hampered functional studies of CAF heterogeneity. We demonstrate that our newly-generated CAF biobank contains three FAP + -fibroblast subtypes, each with unique molecular and functional traits. Cultures with an early-activated phenotype expressed the highest levels of AR and exhibited AR-dependent growth. Consistently, stromal cells expressing early-activation markers co-expressed nuclear AR in clinical specimens and were enriched in pre-neoplastic lesions/low-grade PCa. Conversely, myofibroblastic CAF (myCAF), which expressed low AR levels in vitro and in vivo and were proliferatively-insensitive to AR signaling modulation, constituted the predominant CAF subpopulation in stromogenic high-grade PCa and castration-resistant LACP9 patient-derived xenografts. Exacerbation of the myCAF state upon castration of LAPC9-bearing hosts underscored these findings. Mechanistically, AR loss in myCAF was driven by an NFkB-TGFb1-YAP1 axis, whose combined targeting synergistically repressed myofibroblastic hallmarks and impaired autophagic flux, effects that were potentiated by enzalutamide resulting in myCAF cell death. Collectively, these findings provide a mechanistic rationale for adjuvant targeting of the YAP1-TGFb signaling axis to improve patient outcomes. Biological sciences/Cancer/Cancer microenvironment Biological sciences/Cancer/Urological cancer/Prostate cancer CAF tumor microenvironment patient-derived xenograft stroma autophagy Full Text Additional Declarations The authors declare no competing interests. Supplementary Files BrunneretalSourcedatasupplementaltables.xlsx Supplemental Tables and source data Brunneretalsupplementalfigures08022025.pdf Supplemental Figures BrunneretalSupplementalFigureLegendsNatComm08022025.pdf Supplemental Figure legends Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions 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-3258823","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":228973937,"identity":"f91b5db4-2310-4640-87df-7bcc05897de9","order_by":0,"name":"Elena Brunner","email":"","orcid":"","institution":"Medical University of Innsbruck","correspondingAuthor":false,"prefix":"","firstName":"Elena","middleName":"","lastName":"Brunner","suffix":""},{"id":228973938,"identity":"e7924b66-f483-46e7-b958-5841d6dd269b","order_by":1,"name":"Elisabeth Damisch","email":"","orcid":"https://orcid.org/0000-0003-0833-8412","institution":"Medical University of Innsbruck","correspondingAuthor":false,"prefix":"","firstName":"Elisabeth","middleName":"","lastName":"Damisch","suffix":""},{"id":415393068,"identity":"e88cba2a-7787-401f-828b-b79255612f1c","order_by":2,"name":"Melanie Emma Groninger","email":"","orcid":"","institution":"Medical University of Innsbruck","correspondingAuthor":false,"prefix":"","firstName":"Melanie","middleName":"Emma","lastName":"Groninger","suffix":""},{"id":228973942,"identity":"24194a66-8c92-4e65-b0ae-c09fae783295","order_by":3,"name":"Lukas Nommensen","email":"","orcid":"","institution":"Medical University of Innsbruck","correspondingAuthor":false,"prefix":"","firstName":"Lukas","middleName":"","lastName":"Nommensen","suffix":""},{"id":228973943,"identity":"438d5742-14e0-4579-a381-bd39fc13d564","order_by":4,"name":"Lucy Neumann","email":"","orcid":"","institution":"Medical University of Innsbruck","correspondingAuthor":false,"prefix":"","firstName":"Lucy","middleName":"","lastName":"Neumann","suffix":""},{"id":228973939,"identity":"762a096a-ca5c-41b0-a286-69a6c0c29036","order_by":5,"name":"Georgios Fotakis","email":"","orcid":"","institution":"Medical University of Innsbruck","correspondingAuthor":false,"prefix":"","firstName":"Georgios","middleName":"","lastName":"Fotakis","suffix":""},{"id":228973940,"identity":"efa1c698-7ce3-44a2-9008-333149ae7b19","order_by":6,"name":"Zlatko Trajanoski","email":"","orcid":"https://orcid.org/0000-0002-0636-7351","institution":"Medical University of Innsbruck","correspondingAuthor":false,"prefix":"","firstName":"Zlatko","middleName":"","lastName":"Trajanoski","suffix":""},{"id":228973941,"identity":"aa678924-199a-4530-8c71-1eb481ca37f8","order_by":7,"name":"Georg Schäfer","email":"","orcid":"","institution":"Medical University Innsbruck","correspondingAuthor":false,"prefix":"","firstName":"Georg","middleName":"","lastName":"Schäfer","suffix":""},{"id":228973946,"identity":"467d4cfd-0a71-4146-a7ab-74a81279103d","order_by":8,"name":"Sofia Karkampouna","email":"","orcid":"","institution":"University of Bern","correspondingAuthor":false,"prefix":"","firstName":"Sofia","middleName":"","lastName":"Karkampouna","suffix":""},{"id":228973947,"identity":"9ad4b8b8-4b7e-4cf4-9081-7dbd329ac2a1","order_by":9,"name":"Francesco Bonollo","email":"","orcid":"","institution":"University of Bern","correspondingAuthor":false,"prefix":"","firstName":"Francesco","middleName":"","lastName":"Bonollo","suffix":""},{"id":228973948,"identity":"12694a2e-6010-4b71-bea2-7d315a0c9ee0","order_by":10,"name":"Marianna Kruithof de Julio","email":"","orcid":"https://orcid.org/0000-0002-6085-7706","institution":"University of Bern; Bern University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Marianna","middleName":"Kruithof","lastName":"de Julio","suffix":""},{"id":415393069,"identity":"81bfe1ad-9a22-4fea-8a19-b661d770a7f7","order_by":11,"name":"Natalie Sampson","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0001-9326-8177","institution":"Medical University of Innsbruck","correspondingAuthor":true,"prefix":"","firstName":"Natalie","middleName":"","lastName":"Sampson","suffix":""},{"id":415393070,"identity":"d9355b2e-2c2e-4fab-90b8-87daf58adf53","order_by":12,"name":"Christian Ploner","email":"","orcid":"","institution":"Medical University of Innsbruck","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Ploner","suffix":""}],"badges":[],"createdAt":"2023-08-12 19:30:38","currentVersionCode":2,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-3258823/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-3258823/v2","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":78549401,"identity":"921b6832-f072-4594-b619-7d57933f220f","added_by":"auto","created_at":"2025-03-14 18:53:33","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":7224855,"visible":true,"origin":"","legend":"","description":"","filename":"Brunneretalrevisedmanuscript08022025formattedcopy.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3258823/v2_covered_9442f415-20a8-4238-9f3e-2f67e2045dc9.pdf"},{"id":78548308,"identity":"86c0b332-bda8-4447-8469-d1fc2d8d0b27","added_by":"auto","created_at":"2025-03-14 18:37:29","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":509635,"visible":true,"origin":"","legend":"\u003cp\u003eSupplemental Tables and source data\u003c/p\u003e","description":"","filename":"BrunneretalSourcedatasupplementaltables.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3258823/v2/b373799c2e2c5082f85523bb.xlsx"},{"id":78548310,"identity":"416adf40-c38c-441b-b90a-f1024b480c7e","added_by":"auto","created_at":"2025-03-14 18:37:30","extension":"pdf","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":19320820,"visible":true,"origin":"","legend":"\u003cp\u003eSupplemental Figures\u003c/p\u003e","description":"","filename":"Brunneretalsupplementalfigures08022025.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3258823/v2/9756860ea4fa56e9faebd032.pdf"},{"id":78548309,"identity":"86d8dde4-2f42-4b13-a971-fc0c63695db9","added_by":"auto","created_at":"2025-03-14 18:37:29","extension":"pdf","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":234324,"visible":true,"origin":"","legend":"\u003cp\u003eSupplemental Figure legends\u003c/p\u003e","description":"","filename":"BrunneretalSupplementalFigureLegendsNatComm08022025.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3258823/v2/3029b38a1d23004e0a04657d.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eUnraveling the YAP1-TGFb1 axis: a key driver of androgen receptor loss in prostate cancer-associated fibroblasts\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":"CAF, tumor microenvironment, patient-derived xenograft, stroma, autophagy","lastPublishedDoi":"10.21203/rs.3.rs-3258823/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3258823/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eDue to their pivotal roles in tumor progression and therapy resistance, cancer-associated fibroblasts (CAF) are considered key therapeutic targets with loss of stromal androgen receptor (AR) a poorly understood hallmark of aggressive prostate cancer (PCa). A paucity of pre-clinical models however has hampered functional studies of CAF heterogeneity.\u003cstrong\u003e \u003c/strong\u003eWe demonstrate that our newly-generated CAF biobank contains three FAP\u003csup\u003e+\u003c/sup\u003e-fibroblast subtypes, each with unique molecular and functional traits. Cultures with an early-activated phenotype expressed the highest levels of AR and exhibited AR-dependent growth. Consistently, stromal cells expressing early-activation markers co-expressed nuclear AR in clinical specimens and were enriched in pre-neoplastic lesions/low-grade PCa. Conversely, myofibroblastic CAF (myCAF), which expressed low AR levels \u003cem\u003ein vitro \u003c/em\u003eand \u003cem\u003ein vivo \u003c/em\u003eand were proliferatively-insensitive to AR signaling modulation, constituted the predominant CAF subpopulation in stromogenic high-grade PCa and castration-resistant LACP9 patient-derived xenografts. Exacerbation of the myCAF state upon castration of LAPC9-bearing hosts underscored these findings. Mechanistically, AR loss in myCAF was driven by an NFkB-TGFb1-YAP1 axis, whose combined targeting synergistically repressed myofibroblastic hallmarks and impaired autophagic flux, effects that were potentiated by enzalutamide resulting in myCAF cell death. Collectively, these findings provide a mechanistic rationale for adjuvant targeting of the YAP1-TGFb signaling axis to improve patient outcomes.\u003c/p\u003e","manuscriptTitle":"Unraveling the YAP1-TGFb1 axis: a key driver of androgen receptor loss in prostate cancer-associated fibroblasts","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2025-03-14 18:37:25","doi":"10.21203/rs.3.rs-3258823/v2","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}},{"code":1,"date":"2023-08-26 01:42:50","doi":"10.21203/rs.3.rs-3258823/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":"bbd6d889-184e-4e55-b811-ca0a043fdc5f","owner":[],"postedDate":"March 14th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":44295206,"name":"Biological sciences/Cancer/Cancer microenvironment"},{"id":44295207,"name":"Biological sciences/Cancer/Urological cancer/Prostate cancer"}],"tags":[],"updatedAt":"2025-03-14T18:37:25+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-14 18:37:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-3258823","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3258823","identity":"rs-3258823","version":["v2"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}