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A key mechanism underlying this plasticity is asymmetric cell division (ACD), in which CSCs generate one self-renewing stem cell and one differentiated daughter. This review integrates intrinsic regulators—polarity complexes, cell fate determinants, and spindle orientation—with extrinsic tumor microenvironment cues. It links ACD to heterogeneity, therapy resistance, and quiescent drug-tolerant CSC emergence across multiple malignancies, and highlights pharmacologic disruption of ACD pathways as a therapeutic vulnerability.",{"@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":35,"@type":76,"position":81},"https://docshare.wps.com/document/healthcare/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/targeting-asymmetric-division-in-cancer-stem-cells-implications-for-relapse-and-resistance/374913/",{"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/targeting-asymmetric-division-in-cancer-stem-cells-implications-for-relapse-and-resistance/374913.png","ImageObject",300,407,{"name":92,"@type":93},"kopisore","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-29","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":39},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What role does asymmetric cell division (ACD) play in cancer stem cells?","Question",{"text":112,"@type":113},"ACD allows cancer stem cells to produce one self-renewing stem cell and one differentiated daughter cell, supporting tumor plasticity and heterogeneity.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How does ACD contribute to relapse and therapy resistance?",{"text":117,"@type":113},"The review links ACD to tumor heterogeneity and the emergence of quiescent, drug-tolerant CSCs, which can underlie poor responses and relapse.",{"name":119,"@type":110,"acceptedAnswer":120},"Which therapeutic strategies are mentioned for targeting ACD in cancer?",{"text":121,"@type":113},"Recent efforts highlighted include using inhibitors of NOTCH, WNT, AURORA kinases, and MSI1 to disrupt or redirect ACD.","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},374913,1790254024,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":39,"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},962090880963,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","Latifi et al. Cancer Cell International (2025) 25:434  \n[https://doi.org/10.1186/s12935-025-04052-x](https://doi.org/10.1186/s12935-025-04052-x)  \nCancer Cell International  \nREVIEW Open Access  \nTargeting asymmetric division in cancer stem  cells: implications for relapse and resistance  \nMona Latifi 1,2*, Mahsa Sani3,4 and Farnaz Sani3  \nAbstract  \nCancer stem cells (CSCs) represent a resilient subpopulation within tumors, capable of driving progression, metastasis, and recurrence. One mechanism that enables this plasticity is asymmetric cell division (ACD), a process by which CSCs generate both a self-renewing stem cell and a differentiated daughter cell. While traditionally associated with tissue development, ACD is now recognized as a dynamic and regulated feature of cancer biology, particularly in response to stress conditions such as hypoxia and radiation. In this review, we provide a comprehensive and mechanistic synthesis of how intrinsic factors such as polarity complexes, cell fate determinants (CFDs), spindle orientation cooperate with extrinsic cues from the tumor microenvironment to orchestrate ACD in CSCs. We explore how this process contributes to tumor heterogeneity, therapy resistance, and the emergence of quiescent, drug-tolerant CSCs across multiple malignancies, including brain, breast, colorectal, and hematologic cancers. Importantly, we highlight recent efforts to pharmacologically disrupt or redirect ACD using inhibitors of NOTCH, WNT, AURORA kinases, and MSI1, presenting ACD as a therapeutic vulnerability rather than a static trait. By shifting the focus from CSC markers to division mode, this review introduces a novel conceptual framework for targeting tumor hierarchy and plasticity. Understanding and manipulating ACD offers a promising frontier in precision oncology-one where altering the balance of cell fate decisions could limit relapse, reduce intratumoral complexity, and enhance long-term treatment outcomes.  \nKeywords Cancer stem cells, Asymmetric cell division, Stemness and differentiation, Tumor heterogeneity  \n*Correspondence:  \nMona Latifi  \n[mona.latifi@hci.utah.edu](mona.latifi@hci.utah.edu)  \n1Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA  \n2Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, UT 84132, USA  \n3Shiraz Institute for Stem Cell & Regenerative Medicine, Shiraz University of Medical Sciences, Shiraz, Iran  \n4Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences, Shiraz, Iran  \nIntroduction  \nCancer, often referred to as “the emperor of all maladies,”remains one of the most lethal diseases in human history. Despite significant advancements in cancer treatment, the disease remains largely uncurable due to its intratumoral heterogeneity [1]. Solid tumors exhibit substantial cellular diversity, where some cells respond well to therapy, while others show resistance. Notably, a distinct subpopulation of tumor cells is inherently resistant to treatment, making cancer therapy particularly challenging. These rare and resilient cells, known as cancer stem cells (CSCs), are the primary cancerous cells present atthe onset of tumor formation [2].  \nCSCs exhibit essential properties such as multipotency, self-renewal, clonogenicity, and the ability to proliferate,  \n© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article ","cbCaipcrmx26te5R","https://ap.wps.com/l/cbCaipcrmx26te5R","pdf",5573906,25,"English","# Introduction\n## Cancer stem cells and treatment resistance\n## Asymmetric cell division overview","[{\"question\":\"What role does asymmetric cell division (ACD) play in cancer stem cells?\",\"answer\":\"ACD allows cancer stem cells to produce one self-renewing stem cell and one differentiated daughter cell, supporting tumor plasticity and heterogeneity.\"},{\"question\":\"How does ACD contribute to relapse and therapy resistance?\",\"answer\":\"The review links ACD to tumor heterogeneity and the emergence of quiescent, drug-tolerant CSCs, which can underlie poor responses and relapse.\"},{\"question\":\"Which therapeutic strategies are mentioned for targeting ACD in cancer?\",\"answer\":\"Recent efforts highlighted include using inhibitors of NOTCH, WNT, AURORA kinases, and MSI1 to disrupt or redirect ACD.\"}]","Targeting asymmetric division in cancer stem cells: implications for relapse and resistance | PDF",1790202739,63]