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Metastasis is dependent on collective invasion—a developmental process exploited by many epithelial cancers to establish secondary tumours and promote widespread disease. The key drivers of collective invasion are “Leader Cells”, a functionally distinct subpopulation of cells that direct migration, cellular contractility, and lead trailing or follower cells. Emerging evidence links leader cells to a hybrid epithelial–mesenchymal transition state, phenotypic plasticity, chemotherapeutic resistance, and immune evasion, positioning them as versatile targets for new therapies.",{"@graph":69,"@context":123},[70,84,106],{"@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/leader-cells-invade-and-evadethe-frontline-of-cancer-progression/340256/",{"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/leader-cells-invade-and-evadethe-frontline-of-cancer-progression/340256.png","ImageObject",300,407,{"name":92,"@type":93},"Sage","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-28","2026-09-22",true,{"@type":102,"interactionType":103,"userInteractionCount":105},"InteractionCounter",{"@type":104},"ViewAction",11,{"@type":107,"mainEntity":108},"FAQPage",[109,115,119],{"name":110,"@type":111,"acceptedAnswer":112},"Why is metastasis so lethal across cancers?","Question",{"text":113,"@type":114},"Metastasis is described as the leading cause of cancer-related deaths across malignancies, driven by dissemination from a primary tumour to peripheral sites.","Answer",{"name":116,"@type":111,"acceptedAnswer":117},"What are leader cells and what do they do in collective invasion?",{"text":118,"@type":114},"Leader cells are a functionally distinct subpopulation at the front of a migrating cluster that direct migration, cellular contractility, and the behavior of trailing follower cells.",{"name":120,"@type":111,"acceptedAnswer":121},"How do leader cells contribute to therapy failure and immune evasion?",{"text":122,"@type":114},"The review highlights emerging evidence that metastasis-promoting leader cells are involved in chemotherapeutic resistance and immune evasion, supporting their value as therapy targets.","https://schema.org",{"og:url":83,"og:type":125,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":127,"canonical":83},"index,follow",{"doc_id":129,"site_id":62},340256,1790647733,{"code":4,"msg":5,"data":132},{"doc_id":129,"user_id":133,"nickname":92,"user_avatar":134,"doc_module":4,"category_id":34,"category_name":35,"doc_title":65,"doc_description":67,"doc_content":135,"file_id":136,"file_url":137,"file_type":138,"file_size":139,"view_count":105,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":140,"language":141,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":142,"faqs":143,"seo_title":144,"seo_description":67,"update_tm":145,"read_time":146},687197207057,"https://ap-avatar.wpscdn.com/davatar_29158cc5080c5b710cf443261637dec0","Review  \nLeader Cells: Invade and Evade—The Frontline of Cancer Progression  \nBrittany R. Doran 1,2, Laura R. Moffitt 1,2, Amy L. Wilson 1,2, Andrew N. Stephens 1,2 and Maree Bilandzic 1,2, *  \nCitation: Doran, B.R.; Moffitt, L.R.; Wilson, A.L.; Stephens, A.N.; Bilandzic, M. Leader Cells: Invade and Evade—The Frontline of Cancer Progression. Int. J. Mol. Sci. 2024, 25, 10554. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms251910554  \nAcademic Editor: Carlos Cabañas  \nReceived: 29 August 2024  \nRevised: 25 September 2024  \nAccepted: 26 September 2024  \nPublished: 30 September 2024  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Hudson Institute of Medical Research, Clayton 3168, Australia; [brittany.doran@monash.edu](brittany.doran@monash.edu) (B.R.D.);  \nlaura.moffitt@hudson.org.au (L.R.M.); amy.wilson@hudson.org.au (A.L.W.);  \n[andrew.stephens@cleodx.com](andrew.stephens@cleodx.com) (A.N.S.)  \n2 Department of Molecular and Translational Sciences, Monash University, Clayton 3168, Australia  \n* [Correspondence: maree.bilandzic@hudson.org.au](Correspondence: maree.bilandzic@hudson.org.au)  \nAbstract: Metastasis is the leading cause of cancer-related mortality; however, a complete understanding of the molecular programs driving the metastatic cascade is lacking. Metastasis is dependent on collective invasion—a developmental process exploited by many epithelial cancers to establish secondary tumours and promote widespread disease. The key drivers of collective invasion are “Leader Cells”, a functionally distinct subpopulation of cells that direct migration, cellular contractility, and lead trailing or follower cells. While a significant body of research has focused on leader cell biology in the traditional context of collective invasion, the influence of metastasis-promoting leader cells is an emerging area of study. This review provides insights into the expanded role of leader cells, detailing emerging evidence on the hybrid epithelial–mesenchymal transition (EMT) state and the phenotypical plasticity exhibited by leader cells. Additionally, we explore the role of leader cells in chemotherapeutic resistance and immune evasion, highlighting their potential as effective and diverse targets for novel cancer therapies.  \nKeywords: leader cell; collective invasion; cancer; keratin 14; chemoresistance; metastasis  \n1. Introduction  \nMetastasis is a complex, multi-step process that facilitates the dissemination of cancer cells from a primary tumour to peripheral sites and is the leading cause of cancer-related deaths across all malignancies [1] . Despite the identification of key genetic mutations and signalling pathways involved in promoting metastasis, the precise mechanisms by which these drivers facilitate spread are not fully elucidated. Numerous studies have identified essential mediators of epithelial–mesenchymal transition (EMT), enabling cancer cells to acquire migratory and invasive properties [2]; however, the mechanisms underlying the transition of epithelial cells during malignant transformation, in a cancer type-and stage-specific manner, remain an active area of investigation [3] .  \nLarge scale coordinated cellular translocation is a fundamental process enabling the establishment and complex organisation of tissues and organs during embryogenesis and is essential for wound healing and angiogenesis in adult tissues [4,5] . Epithelial cells exist as large, immobile sheets maintained by stable, E-cadherin-based adherens junctions with neighbouring cells [6] . Under normal circumstances, signals promoting relocation induce epithelial cells to undergo single-cell migration by a","cbCailOTsKg9pUdA","https://ap.wps.com/l/cbCailOTsKg9pUdA","pdf",1417309,14,"English","# Abstract\n# Introduction\n## Metastasis as a multi-step process\n## EMT and the molecular programs enabling invasion\n## Collective migration and leader–follower cell organization","[{\"question\":\"Why is metastasis so lethal across cancers?\",\"answer\":\"Metastasis is described as the leading cause of cancer-related deaths across malignancies, driven by dissemination from a primary tumour to peripheral sites.\"},{\"question\":\"What are leader cells and what do they do in collective invasion?\",\"answer\":\"Leader cells are a functionally distinct subpopulation at the front of a migrating cluster that direct migration, cellular contractility, and the behavior of trailing follower cells.\"},{\"question\":\"How do leader cells contribute to therapy failure and immune evasion?\",\"answer\":\"The review highlights emerging evidence that metastasis-promoting leader cells are involved in chemotherapeutic resistance and immune evasion, supporting their value as therapy targets.\"}]","Leader Cells: Invade and Evade—The Frontline of Cancer Progression | PDF",1790035296,35]