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Tumor formation involves epithelial-mesenchymal transition (EMT), enabling metastasis and cellular plasticity. While drug combinations have been reported to transform cancer cells into adipocytes, the molecular network mechanisms remain unclear. This study uses a systems biology framework combining mathematical modeling and molecular experiments to map the CAC landscape, identify attractor states, and derive landscape-controlled drug-combination strategies that promote CAC, validated across different cell lines.",{"@graph":69,"@context":114},[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/energy-landscape-reveals-the-underlying-mechanism-of-cancer-adipose-conversion-in-gene-network-models/331497/",{"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/energy-landscape-reveals-the-underlying-mechanism-of-cancer-adipose-conversion-in-gene-network-models/331497.png","ImageObject",300,407,{"name":92,"@type":93},"Eden","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-11-06","2026-09-21",true,{"@type":102,"interactionType":103,"userInteractionCount":24},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108],{"name":109,"@type":110,"acceptedAnswer":111},"What therapeutic strategies does the study propose and verify?","Question",{"text":112,"@type":113},"Using a landscape control approach, it identifies two new drug-combination strategies intended to promote CAC, and then verifies the predictions with molecular experiments in different cell lines.","Answer","https://schema.org",{"og:url":83,"og:type":116,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":118,"canonical":83},"index,follow",{"doc_id":120,"site_id":62},331497,1792178281,{"code":4,"msg":5,"data":123},{"doc_id":120,"user_id":124,"nickname":92,"user_avatar":125,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":126,"file_id":127,"file_url":128,"file_type":129,"file_size":130,"view_count":24,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":131,"language":132,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":133,"faqs":134,"seo_title":135,"seo_description":67,"update_tm":136,"read_time":137,"preview_page_count":4},1374391974468,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","RESEARCH ARTICLE  \n[www.advancedscience.com](www.advancedscience.com)  \nEnergy Landscape Reveals the Underlying Mechanism of Cancer-Adipose Conversion in Gene Network Models  \nZihao Chen, Jia Lu, Xing-Ming Zhao, Haiyang Yu,* and Chunhe Li*  \nCancer is a systemic heterogeneous disease involving complex molecular networks. Tumor formation involves an epithelial-mesenchymal transition (EMT), which promotes both metastasis and plasticity of cancer cells. Recent experiments have proposed that cancer cells can be transformed into adipocytes via a combination of drugs. However, the underlying mechanisms for how these drugs work, from a molecular network perspective, remain elusive. To reveal the mechanism of cancer-adipose conversion (CAC), this study adopts a systems biology approach by combing mathematical modeling and molecular experiments, based on underlying molecular regulatory networks. Four types of attractors are identified, corresponding to epithelial (E), mesenchymal (M), adipose (A) and partial/intermediate EMT (P) cell states on the CAC landscape. Landscape and transition path results illustrate that intermediate states play critical roles in the cancer to adipose transition. Through a landscape control approach, two new therapeutic strategies for drug combinations are identified, that promote CAC. These predictions areverified by molecular experiments in different cell lines. The combined computational and experimental approach provides a powerful tool to explore molecular mechanisms for cell fate transitions in cancer networks. The results reveal underlying mechanisms of intermediate cell states that govern the CAC, and identified new potential drug combinations to induce cancer adipogenesis.  \n1. Introduction  \nCancer formation is a complex process with multiple transition states governed by underlying gene regulatory networks. [1,2] Tumor cells undergo both epithelialmesenchymal transition (EMT) and mesenchymal-epithelial transition (MET), to achieve plasticity and metastasis. [3–6] The EMT process enhances the plasticity of cancer cells, and is believed to facilitate cancer metastasis. [7–9] It has been proposed that cells undergoing EMT and/or MET enter a state of heightened plasticity, potentially providing a critical window for therapeutic intervention. [7,10,11] For example, recent work suggested that cancer cells can be transformed into adipocytes through aspecific combination of treatments. [12,13] However, the underlying mechanisms driving this cancer-adipose conversion (CAC) are unknown at the present time. This motivated us to explore the underlying molecular regulatory networks that govern cell fate decisions in CAC.  \nDynamical modeling approaches provide effective tools to analyze the functions and behaviors of biological networks,  \ne.g., for EMT and cancer networks. [14–18] Meanwhile, a stochastic description needs to be considered in cell fate decisions, owing to intrinsic fluctuations within cells and external fluctuations acting upon cells. [19,20] Energy landscape theory, which builds  \nZ. Chen, C. Li  \nShanghai Center for Mathematical Sciences Fudan University  \nShanghai 200433, China  \nE-mail: [chunheli@fudan.edu.cn](chunheli@fudan.edu.cn)  \nZ. Chen, X. M. Zhao, C. Li  \nInstitute of Science and Technology for Brain-Inspired Intelligence Fudan University  \nShanghai 200433, China  \nThe ORCID identification number(s) for the author(s) of this article  \ncan be found under [https://doi.org/10.1002/advs.202404854](https://doi.org/10.1002/advs.202404854)[ ](https://doi.org/10.1002/advs.202404854)© 2024 The Author(s). Advanced Science published by Wiley-VCH GmbH. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.  \nDOI: 10.1002/advs.202404854  \nJ. Lu, H. Yu  \nState Key Laboratory of Component-based Chinese Medicine Tianjin University of Traditional Chinese Medicine ","cbCaih4rqvaTxrp0","https://ap.wps.com/l/cbCaih4rqvaTxrp0","pdf",6918534,14,"English","# Introduction\n## Cancer progression, EMT/MET, and cellular plasticity\n## Energy landscape theory and dynamical transition paths\n# Study approach (systems biology, modeling, experiments)","[{\"question\":\"What therapeutic strategies does the study propose and verify?\",\"answer\":\"Using a landscape control approach, it identifies two new drug-combination strategies intended to promote CAC, and then verifies the predictions with molecular experiments in different cell lines.\"}]","Energy Landscape Reveals the Underlying Mechanism of Cancer-Adipose Conversion in Gene Network Models | PDF",1789993589,35]