[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"detail-sidebar-cat-0-en-105":3,"doc-seo-353044-105":59,"doc-detail-353044-en":130},{"code":4,"msg":5,"data":6},0,"success",[7,13,18,23,28,33,38,43,48,51,55],{"id":8,"doc_module":4,"doc_module_name":9,"category_name":10,"show_sort_weight":11,"slug":12},1,"Document","Story & Novel",90,"story-novel",{"id":14,"doc_module":4,"doc_module_name":9,"category_name":15,"show_sort_weight":16,"slug":17},2,"Literature",80,"literature",{"id":19,"doc_module":4,"doc_module_name":9,"category_name":20,"show_sort_weight":21,"slug":22},4,"Exam",70,"exam",{"id":24,"doc_module":4,"doc_module_name":9,"category_name":25,"show_sort_weight":26,"slug":27},5,"Comic",60,"comic",{"id":29,"doc_module":4,"doc_module_name":9,"category_name":30,"show_sort_weight":31,"slug":32},6,"Technology",50,"technology",{"id":34,"doc_module":4,"doc_module_name":9,"category_name":35,"show_sort_weight":36,"slug":37},7,"Healthcare",40,"healthcare",{"id":39,"doc_module":4,"doc_module_name":9,"category_name":40,"show_sort_weight":41,"slug":42},8,"Research & Report",30,"research-report",{"id":44,"doc_module":4,"doc_module_name":9,"category_name":45,"show_sort_weight":46,"slug":47},9,"Religion & Spirituality",20,"religion-spirituality",{"id":46,"doc_module":4,"doc_module_name":9,"category_name":49,"show_sort_weight":46,"slug":50},"World Cup","world-cup",{"id":52,"doc_module":4,"doc_module_name":9,"category_name":53,"show_sort_weight":52,"slug":54},10,"Lifestyle","lifestyle",{"id":56,"doc_module":4,"doc_module_name":9,"category_name":57,"show_sort_weight":24,"slug":58},19,"General","general",{"code":4,"msg":60,"data":61},"ok",{"site_id":62,"language":63,"slug":64,"title":65,"keywords":66,"description":67,"schema_data":68,"social_meta":123,"head_meta":125,"extra_data":127,"updated_unix":129},105,"en","game-of-clones-decipher-lineage-plasticity-in-hormone-driven-cancers","Game of clones - decipher lineage plasticity in hormone-driven cancers","","Hormone-dependent cancers including prostate, breast, and endometrial tumors rely on nuclear hormone receptors to maintain lineage identity and support growth. Targeted therapies against androgen, estrogen, or progesterone signaling often work initially, but selective pressure eventually produces resistance via lineage plasticity, where tumor cells abandon native identity and adopt alternative fates. The review outlines regulatory programs that control stability, directionality, and vulnerability of these fate transitions using multi-omics, single-cell/spatial, and AI-driven integration, emphasizing therapeutic opportunities to limit resistance.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/game-of-clones-decipher-lineage-plasticity-in-hormone-driven-cancers/353044/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/game-of-clones-decipher-lineage-plasticity-in-hormone-driven-cancers/353044.png","ImageObject",300,407,{"name":92,"@type":93},"Dipper","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-25","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":81},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What drives resistance in hormone-dependent cancers according to the review?","Question",{"text":112,"@type":113},"Resistance arises not only from genetic alterations but also from lineage plasticity, where tumor cells destabilize lineage identity and switch to alternative cellular fates under therapy pressure.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does the review define cell state and cell fate?",{"text":117,"@type":113},"Cell state is a dynamic, potentially reversible molecular configuration, while cell fate is a stable lineage commitment maintained by sustained regulatory circuits.",{"name":119,"@type":110,"acceptedAnswer":120},"What technologies does the review highlight for studying lineage plasticity?",{"text":121,"@type":113},"It emphasizes integrative multiomics across genomic, transcriptomic, epigenomic, proteomic, and chromatin layers, supported by single-cell and spatial technologies to reveal intermediate states and rare subpopulations.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},353044,1790238705,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":81,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},1374404997633,"https://ap-avatar.wpscdn.com/davatar_a8503ba1806abce46bf441b54a3ca4cd","Cellular and Molecular Life Sciences (2026) 83:236  \n[https://doi.org/10.1007/s00018-026-06171-8](https://doi.org/10.1007/s00018-026-06171-8) Cellular and Molecular Life Sciences  \nREVIEW  \nGame of clones: decipher lineage plasticity in hormone-driven cancers  \nAmanda Leonita1,2 · Siyuan Cheng1 · Joshua Warrick2,3 · Isaac Yi Kim1,3 · Su Deng1,2,3 · Ping Mu1,2,3  \nReceived: 27 January 2026 / Revised: 26 February 2026 / Accepted: 28 February 2026 © The Author(s) 2026  \nAbstract  \nHormone-dependent cancers such as prostate, breast, and endometrial carcinomas rely on nuclear hormone receptors to sustain lineage identity and growth. Therapies targeting androgen, estrogen, or progesterone signaling are initially effective but ultimately impose selective pressures that drive resistance through lineage plasticity, the ability of tumor cells to abandon their native identity and adopt alternative cellular fates. While the biological consequences of lineage plasticity are increasingly recognized, a major challenge lies in defining the regulatory programs that govern these cell fate transitions and determine their stability, directionality, and therapeutic vulnerability. In this review, we focus on the regulatory modules that underlie lineage plasticity in hormone-driven cancers. We highlight how integrative multiomics approaches spanning genomic, transcriptomic, epigenomic, proteomic, and chromatin-level layers have enabled the identification of transcriptional and epigenetic programs that destabilize lineage fidelity. We discuss how single-cell and spatial technologies have revealed intermediate states, rare subpopulations, and microenvironmental influences that shape plasticity trajectories. Finally, we emphasize the role of artificial intelligence and machine learning as integrative tools toreconstruct gene regulatory circuits, infer fate transitions, and connect molecular programs to phenotypic outcomes. By synthesizing these biological insights across experimental and computational modalities, we propose a conceptual framework for understanding lineage plasticity in hormone-driven cancers, with emphasis on prostate and breast malignancies. This integrated perspective highlights how regulatory programs governing cell identity can be revealed, perturbed, and potentially constrained, offering opportunities to identify biomarkers, expose therapeutic vulnerabilities, and ultimately translate mechanistic understanding into strategies that limit resistance.  \nKeywords Lineage plasticity · Hormone-dependent cancers · Regulatory modules · Multi-omics approaches · Artificial intelligence  \nIntroduction  \nHormone-dependent cancers, including prostate, breast, and endometrial carcinomas, are some of the most common and clinically significant malignancies worldwide [90] . These tumors originate from hormone-responsive epithelial tissues that rely on nuclear hormone receptors to  \n􀀍 Ping Mu [ping.mu@yale.edu](ping.mu@yale.edu)  \n1 Department of Urology, Yale University School of Medicine, New Haven, CT 06511, USA  \n2 Department of Pathology, Yale University School of Medicine, New Haven, CT 06511, USA  \n3 Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06511, USA  \ndrive lineage-specific gene expression programs that support growth, differentiation, and survival. As such hormone signaling through receptors, such as the androgen receptor (AR), estrogen receptor alpha (ERa), and progesterone receptor (PR), represents a central therapeutic vulnerability. In prostate cancer, standard-of-care involves utilizing androgen deprivation therapy (ADT) and next-generation AR-targeted therapies to suppress androgen signaling [95, 99] . Breast cancer treatments frequently employ endocrine therapies such as selective estrogen receptor modulators (SERMs), aromatase inhibitors, or selective estrogen receptor degraders (SERDs) [80] .  \nHistorically, resistance to targeted cancer therapies has been understood through a genetic lens driven by t","cbCaifGwwB2k06UF","https://ap.wps.com/l/cbCaifGwwB2k06UF","pdf",1504175,17,"English","# Introduction\n## Hormone-dependent cancers and therapeutic vulnerability\n## Resistance beyond genetic mechanisms\n## Cell state and cell fate framework\n## Multi-omics and integrative investigation","[{\"question\":\"What drives resistance in hormone-dependent cancers according to the review?\",\"answer\":\"Resistance arises not only from genetic alterations but also from lineage plasticity, where tumor cells destabilize lineage identity and switch to alternative cellular fates under therapy pressure.\"},{\"question\":\"How does the review define cell state and cell fate?\",\"answer\":\"Cell state is a dynamic, potentially reversible molecular configuration, while cell fate is a stable lineage commitment maintained by sustained regulatory circuits.\"},{\"question\":\"What technologies does the review highlight for studying lineage plasticity?\",\"answer\":\"It emphasizes integrative multiomics across genomic, transcriptomic, epigenomic, proteomic, and chromatin layers, supported by single-cell and spatial technologies to reveal intermediate states and rare subpopulations.\"}]","Game of clones - decipher lineage plasticity in hormone-driven cancers | PDF",1790102711,43]