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The limited efficacy of current treatments in patients with primary liver cancers (PLCs) is linked to high heterogeneity across hepatocellular carcinoma and intrahepatic cholangiocarcinoma, shaped over time by cancer stem cells (CSCs) through (epi)genetic changes and microenvironmental influences. These processes promote plasticity and resistance, increasing the need for personalized therapies guided by biomarkers and CSC targeting. Progress in patient-derived liver cancer cell lines and organoids (PDOs) offers patient-avatar models that preserve key in vivo heterogeneity, enabling drug screening and response testing. This review summarizes advances in constructing PLC-derived PDO models, emphasizing CSC roles and discussing limitations such as culture conditions, reproducibility, and scalability.",{"@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/state-of-the-art-liver-cancer-organoids-modeling-cancer-stem-cell-heterogeneity-for-personalized-treatment-journal-article/367246/",{"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/state-of-the-art-liver-cancer-organoids-modeling-cancer-stem-cell-heterogeneity-for-personalized-treatment-journal-article/367246.png","ImageObject",300,407,{"name":92,"@type":93},"Riley","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-10-27","2026-09-23",true,{"@type":102,"interactionType":103,"userInteractionCount":44},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"Why is liver cancer treatment difficult in primary liver cancers (PLCs)?","Question",{"text":112,"@type":113},"Limited success of current therapies is associated with the high heterogeneity of tumors, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma. This heterogeneity evolves over time as CSCs adapt to genetic/epigenetic and microenvironmental changes, supporting therapy resistance.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"How do cancer stem cells (CSCs) contribute to therapy resistance?",{"text":117,"@type":113},"CSC sub-populations undergo dynamic evolution and plasticity driven by internal signals (genetic and epigenetic) and external tumor microenvironment and drug-pressure cues. This plasticity enables CSCs to differentiate into resistant tumor cell types.",{"name":119,"@type":110,"acceptedAnswer":120},"What role do patient-derived organoids (PDOs) play in personalized treatment research?",{"text":121,"@type":113},"PDO cultures can self-assemble and self-renew while retaining inter- and intratumoral heterogeneity from patient tissues. Organoids derived from PLCs act as patient avatars for stratification, drug screening, and efficacy testing in preclinical studies.","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},367246,1790289039,{"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":44,"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":26},1374391975076,"https://ap-avatar.wpscdn.com/avatar/14000253ca4ec9f6853?x-image-process=image/resize,m_fixed,w_180,h_180&k=1783305029341752051","BioDrugs (2025) 39:237–260  \n[https://doi.org/10.1007/s40259-024-00702-0](https://doi.org/10.1007/s40259-024-00702-0)  \nState‑of‑the‑Art Liver Cancer Organoids: Modeling Cancer Stem Cell Heterogeneity for Personalized Treatment  \nJulien Giron‑Michel1,2 · Maël Padelli1,2,3 · Estelle Oberlin1,2 · Hind Guenou1,2 ·  \nJean‑Charles Duclos‑Vallée2,4,5,6  \nAccepted: 21 December 2024 / Published online: 18 January 2025 © The Author(s) 2025  \nAbstract  \nLiver cancer poses a global health challenge with limited therapeutic options. Notably, the limited success of current therapies in patients with primary liver cancers (PLCs) may be attributed to the high heterogeneity of both hepatocellular carcinoma (HCCs) and intrahepatic cholangiocarcinoma (iCCAs). This heterogeneity evolves over time as tumor-initiating stem cells, or cancer stem cells (CSCs), undergo (epi)genetic alterations or encounter microenvironmental changes within the tumor microenvironment. These modifications enable CSCs to exhibit plasticity, differentiating into various resistant tumor cell types. Addressing this challenge requires urgent efforts to develop personalized treatments guided by biomarkers, with a specific focus on targeting CSCs. The lack of effective precision treatments for PLCs is partly due to the scarcity of ex vivo preclinical models that accurately capture the complexity of CSC-related tumors and can predict therapeutic responses. Fortunately, recent advancements in the establishment of patient-derived liver cancer cell lines and organoids have opened new avenues for precision medicine research. Notably, patient-derived organoid (PDO) cultures have demonstrated selfassembly and self-renewal capabilities, retaining essential characteristics of their respective in vivo tissues, including both inter-and intratumoral heterogeneities. The emergence of PDOs derived from PLCs serves as patient avatars, enabling preclinical investigations for patient stratification, screening of anticancer drugs, efficacy testing, and thereby advancing the field of precision medicine. This review offers a comprehensive summary of the advancements in constructing PLC-derived PDO models. Emphasis is placed on the role of CSCs, which not only contribute significantly to the establishment of PDO cultures but also faithfully capture tumor heterogeneity and the ensuing development of therapy resistance. The exploration of PDOs’ benefits in personalized medicine research is undertaken, including a discussion of their limitations, particularly in terms of culture conditions, reproducibility, and scalability.  \n* Julien Giron-Michel [julien.giron-michel@inserm.fr](julien.giron-michel@inserm.fr)  \n1 INSERM UMR-S-MD 1197, Paul-Brousse Hospital, Villejuif, France  \n2 Orsay-Vallée Campus, Paris-Saclay University, Gif-sur-Yvette, France  \n3 Department of Biochemistry and Oncogenetics, Paul Brousse Hospital, AP-HP, Villejuif, France  \n4 INSERM UMR-S 1193, Paul Brousse Hospital, Villejuif, France  \n5 Hepato-Biliary Department, Paul Brousse Hospital, APHP, Villejuif, France  \n6 Fédération Hospitalo-Universitaire (FHU) Hepatinov, Villejuif, France  \n1 Introduction  \nThe global cancer burden is responsible for nearly 10 million deaths per year and is expected to increase. Among the different organs affected, the liver is the sixth most common site of primary cancer in humans with approximately 905,000 cases in 2020 [1] . Primary liver cancers (PLCs) include a heterogeneous group of tumors with distinct histological features and poor prognosis rates: hepatocellular carcinoma (HCCs) represents 80–85% of all PLCs, followed by intrahepatic cholangiocarcinoma (iCCAs) and a combined hepatocellular-cholangiocarcinoma subtype (CHCs) . While hepatitis B virus (HBV) and hepatitis C virus (HCV) infections remain pivotal external risk factors, the significant rise in PLC cases is also attributed to excessive alcohol consumption and the related conditions of metabolic syndrome, obesity, type 2 diabetes, and","cbCaisoDgIwiW03o","https://ap.wps.com/l/cbCaisoDgIwiW03o","pdf",2755454,24,"English","# Abstract\n# Introduction","[{\"question\":\"Why is liver cancer treatment difficult in primary liver cancers (PLCs)?\",\"answer\":\"Limited success of current therapies is associated with the high heterogeneity of tumors, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma. This heterogeneity evolves over time as CSCs adapt to genetic/epigenetic and microenvironmental changes, supporting therapy resistance.\"},{\"question\":\"How do cancer stem cells (CSCs) contribute to therapy resistance?\",\"answer\":\"CSC sub-populations undergo dynamic evolution and plasticity driven by internal signals (genetic and epigenetic) and external tumor microenvironment and drug-pressure cues. This plasticity enables CSCs to differentiate into resistant tumor cell types.\"},{\"question\":\"What role do patient-derived organoids (PDOs) play in personalized treatment research?\",\"answer\":\"PDO cultures can self-assemble and self-renew while retaining inter- and intratumoral heterogeneity from patient tissues. Organoids derived from PLCs act as patient avatars for stratification, drug screening, and efficacy testing in preclinical studies.\"}]","State-of-the-Art Liver Cancer Organoids: Modeling Cancer Stem Cell Heterogeneity for Personalized Treatment - Journal Article | PDF",1790169874]