Integrated metabolic and transcriptomic landscapes reveal an obligate reliance on exogenous steroid conversion for prostate cancer survival

Integrated metabolic and transcriptomic landscapes reveal an obligate reliance on exogenous steroid conversion for prostate cancer survival | 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 Integrated metabolic and transcriptomic landscapes reveal an obligate reliance on exogenous steroid conversion for prostate cancer survival Amit Pandey, Jibira Yakubu, Therina du Toit This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9358922/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 Castration-resistant prostate cancer (CRPC) survives androgen deprivation, a mechanism widely attributed to autonomous de novo steroidogenesis. Despite the clinical deployment of CYP17A1 inhibitors, the metabolic fidelity of the models underpinning this "tumor-as-gonad" dogma remains controversial. Here, integrating high-resolution liquid chromatography-mass spectrometry with transcriptomics across diverse prostate cancer models, we demonstrate that malignant cell lines universally lack autonomous steroidogenic capacity due to the transcriptional silencing of CYP17A1. Instead, these models operate as high-efficiency precursor "converters" by upregulating HSD3B1 and AKR1C3. Clinical stratification of 844 Prostate Adenocarcinoma patients corroborated this precursor-dependent phenotype. We identify a critical divergence: AR-High tumors rely on oxidative phosphorylation, whereas the transition to an AR-Low state is marked by extensive lineage plasticity. Strikingly, a neuroendocrine plasticity score inversely correlates with AR flux and independently predicts clinical progression (HR=2.41, p=0.024). Our findings redefine CRPC metabolism, dictating a therapeutic shift toward targeting downstream precursor conversion and adaptive lineage plasticity. Health sciences/Urology/Prostate Biological sciences/Cancer/Cancer metabolism Biological sciences/Biochemistry/Enzymes/Oxidoreductases Castration-resistant prostate cancer Intracrine steroidogenesis Androgen receptor signaling Lineage plasticity Metabolic rewiring Liquid chromatography-mass spectrometry Multi-omics Precursor conversion Full Text Additional Declarations There is NO Competing Interest. 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. 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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-9358922","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":620402239,"identity":"1e017f21-daea-4ec3-a491-a7b701788a63","order_by":0,"name":"Amit Pandey","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA6ElEQVRIiWNgGAWjYFACxgYIfYCB8QEDg0QCkMlGSEtjA1QLswGRWmDWHGBgkwBShLXwTzvc/oBxh10e3/Ees2reHRZ5/AzMzx7g0yJxO7GxgfFMcrHkmTNmt3nPSBRLNrCZG+C1BqyljTlxw40coJY2icQNB3jALsQJ5CFa6hM33H9jVgzSsp+QFgOIlsNAW3jMmMG2MBDQYgjUMiPxzPHEmWfSiiXntkkUSxxmM8OrRe52+oMPH3dUJ/YdP7zxw9u2ujz+9uZneLWAQWIDiOSAhhMzQfUMsMhkf0CM2lEwCkbBKBiBAAB5uU43y+Rv2wAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0001-8331-5902","institution":"University of Bern","correspondingAuthor":true,"prefix":"","firstName":"Amit","middleName":"","lastName":"Pandey","suffix":""},{"id":620402240,"identity":"8acef95e-61d9-48f8-9d1c-1263b63b855f","order_by":1,"name":"Jibira Yakubu","email":"","orcid":"","institution":"University of Bern","correspondingAuthor":false,"prefix":"","firstName":"Jibira","middleName":"","lastName":"Yakubu","suffix":""},{"id":620402241,"identity":"dcaf6be3-a4d9-48b8-9c9b-8bf0a7d8f527","order_by":2,"name":"Therina du Toit","email":"","orcid":"","institution":"University of Bern","correspondingAuthor":false,"prefix":"","firstName":"Therina","middleName":"","lastName":"du Toit","suffix":""}],"badges":[],"createdAt":"2026-04-08 15:26:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9358922/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9358922/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":106961235,"identity":"43a81bc8-0783-4f67-8591-e6b50b49ee8b","added_by":"auto","created_at":"2026-04-15 09:24:47","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2641076,"visible":true,"origin":"","legend":"Article File","description":"","filename":"ManuscriptYakubuetal.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9358922/v1_covered_bf6a0a09-088e-4dd9-aa52-a50a92632921.pdf"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"Integrated metabolic and transcriptomic landscapes reveal an obligate reliance on exogenous steroid conversion for prostate cancer survival","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":"Castration-resistant prostate cancer; Intracrine steroidogenesis; Androgen receptor signaling; Lineage plasticity; Metabolic rewiring; Liquid chromatography-mass spectrometry; Multi-omics; Precursor conversion","lastPublishedDoi":"10.21203/rs.3.rs-9358922/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9358922/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Castration-resistant prostate cancer (CRPC) survives androgen deprivation, a mechanism widely attributed to autonomous de novo steroidogenesis. Despite the clinical deployment of CYP17A1 inhibitors, the metabolic fidelity of the models underpinning this \"tumor-as-gonad\" dogma remains controversial. Here, integrating high-resolution liquid chromatography-mass spectrometry with transcriptomics across diverse prostate cancer models, we demonstrate that malignant cell lines universally lack autonomous steroidogenic capacity due to the transcriptional silencing of CYP17A1. Instead, these models operate as high-efficiency precursor \"converters\" by upregulating HSD3B1 and AKR1C3. Clinical stratification of 844 Prostate Adenocarcinoma patients corroborated this precursor-dependent phenotype. We identify a critical divergence: AR-High tumors rely on oxidative phosphorylation, whereas the transition to an AR-Low state is marked by extensive lineage plasticity. Strikingly, a neuroendocrine plasticity score inversely correlates with AR flux and independently predicts clinical progression (HR=2.41, p=0.024). 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