[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-331739-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-331739-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","engineered-extrachromosomal-oncogene-amplifications-promote-tumorigenesis","Engineered extrachromosomal oncogene amplifications promote tumorigenesis","","Focal gene amplifications are common cancer-associated mutations, yet modeling them in primary cells and animals has been difficult. The article presents a general strategy to engineer large, focal ecDNA-mediated amplifications in temporally controlled ways in cells and mice, coupling ecDNA formation with selectable markers to monitor dynamics under physiological and selective pressures. Engineered Cre-inducible Myc- and Mdm2 ecDNAs accumulate spontaneously, driving proliferation, immortalization, and transformation, and Mdm2 ecDNAs promote liver tumour formation in an autochthonous hepatocellular carcinoma model.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/research-report/","Research & Report",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/engineered-extrachromosomal-oncogene-amplifications-promote-tumorigenesis/331739/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/engineered-extrachromosomal-oncogene-amplifications-promote-tumorigenesis/331739.png","ImageObject",300,407,{"name":42,"@type":43},"Valentina","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-26","2026-09-21",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",10,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What problem does the study address about oncogene amplification modeling?","Question",{"text":63,"@type":64},"It addresses the difficulty of engineering and studying focal gene amplifications in primary cells and model organisms, which has limited accurate preclinical modeling of cancer initiation and progression.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How does the reported strategy control and track ecDNA-driven amplifications?",{"text":68,"@type":64},"It engineers large focal amplifications mediated by extrachromosomal DNAs in a time-controlled manner and couples ecDNA formation with selectable markers to monitor ecDNA-containing cells under different pressures.",{"name":70,"@type":61,"acceptedAnswer":71},"What biological effects do engineered ecDNAs have in primary cells and mice?",{"text":72,"@type":64},"Engineered Myc- and Mdm2-containing ecDNAs accumulate spontaneously, promoting proliferation, immortalization, and transformation; Mdm2-containing ecDNAs also induce tumour formation in an autochthonous hepatocellular carcinoma mouse model.","https://schema.org",{"og:url":32,"og:type":75,"og:title":10,"og:site_name":45,"og:description":12},"article",{"robots":77,"canonical":32},"index,follow",{"doc_id":79,"site_id":7},331739,1790241394,{"code":4,"msg":82,"data":83},"success",[84,88,92,96,101,106,111,115,120,123,126],{"id":22,"doc_module":4,"doc_module_name":25,"category_name":85,"show_sort_weight":86,"slug":87},"Story & Novel",90,"story-novel",{"id":26,"doc_module":4,"doc_module_name":25,"category_name":89,"show_sort_weight":90,"slug":91},"Literature",80,"literature",{"id":33,"doc_module":4,"doc_module_name":25,"category_name":93,"show_sort_weight":94,"slug":95},"Exam",70,"exam",{"id":97,"doc_module":4,"doc_module_name":25,"category_name":98,"show_sort_weight":99,"slug":100},5,"Comic",60,"comic",{"id":102,"doc_module":4,"doc_module_name":25,"category_name":103,"show_sort_weight":104,"slug":105},6,"Technology",50,"technology",{"id":107,"doc_module":4,"doc_module_name":25,"category_name":108,"show_sort_weight":109,"slug":110},7,"Healthcare",40,"healthcare",{"id":112,"doc_module":4,"doc_module_name":25,"category_name":29,"show_sort_weight":113,"slug":114},8,30,"research-report",{"id":116,"doc_module":4,"doc_module_name":25,"category_name":117,"show_sort_weight":118,"slug":119},9,"Religion & Spirituality",20,"religion-spirituality",{"id":118,"doc_module":4,"doc_module_name":25,"category_name":121,"show_sort_weight":118,"slug":122},"World Cup","world-cup",{"id":55,"doc_module":4,"doc_module_name":25,"category_name":124,"show_sort_weight":55,"slug":125},"Lifestyle","lifestyle",{"id":127,"doc_module":4,"doc_module_name":25,"category_name":128,"show_sort_weight":97,"slug":129},19,"General","general",{"code":4,"msg":82,"data":131},{"doc_id":79,"user_id":132,"nickname":42,"user_avatar":133,"doc_module":4,"category_id":112,"category_name":29,"doc_title":10,"doc_description":12,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":55,"is_deleted":4,"is_public":22,"is_downloadable":22,"audit_status":22,"page_count":139,"language":140,"language_code":8,"site_id":7,"html_lang":8,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":12,"update_tm":144,"read_time":145,"preview_page_count":4},13056703020460,"https://ap-avatar.wpscdn.com/avatar/be000253dac470eee5d?_k=1778207105932848923","Article  \n\n| Engineered extrachromosomal oncogene amplifications promote tumorigenesis |  |  |\n| --- | --- | --- |\n| [https://doi.org/10.1038/s41586-024-08318-8](https://doi.org/10.1038/s41586-024-08318-8)\u003Cbr>Received: 22 June 2023 Accepted: 31 October 2024 Published online: 18 December 2024 Open access\u003Cbr> Check for updates | Davide Pradella1,16, Minsi Zhang1,2,16, Rui Gao1,3,16, Melissa A. Yao1,3,16, Katarzyna M. Gluchowska1, Ylenia Cendon-Florez1, Tanmay Mishra1,4, Gaspare La Rocca1, Moritz Weigl1, Ziqi Jiao1,3,\u003Cbr>Hieu H. M. Nguyen1, Marta Lisi5, Mateusz M. Ozimek1, Chiara Mastroleo1, Kevin Chen1,\u003Cbr>Felix Grimm1, Jens Luebeck6, Shu Zhang7,8,9,10, Andrea Alice Zolli1, Eric G. Sun1,11,\u003Cbr>Bhargavi Dameracharla6, Zhengqiao Zhao12, Yuri Pritykin12, Carlie Sigel13, Howard Y. Chang7,8,14, Paul S. Mischel9,10, Vineet Bafna6,15, Cristina R. Antonescu13 & Andrea Ventura1 ✉\u003Cbr>Focal gene amplifications are among the most common cancer-associated mutations1 but have proven challenging to engineer in primary cells and model organisms. Here we describe a general strategy to engineer large (more than 1 Mbp) focal amplifications mediated by extrachromosomal DNAs (ecDNAs)2 in aspatiotemporally controlled manner in cells and in mice. By coupling ecDNA formation with expression of selectable markers, we track the dynamics of ecDNA-containing cells under physiological conditions and in the presence of specific selective pressures. We also apply this approach to generate mice harbouring Cre-inducibleMyc-and Mdm2-containing ecDNAs analogous to those occurring inhuman cancers. Weshowthatthe engineered ecDNAs spontaneously accumulate in primary cells derived from these animals, promoting their proliferation, immortalization and transformation. Finally, we demonstrate the ability of Mdm2-containing ecDNAsto promote tumour formation inan autochthonous mouse model of hepatocellular carcinoma. These findings offer insightsintothe roleofecDNA-mediated gene amplificationsin tumorigenesis. We anticipate that this approach will be valuable for investigating further unresolved aspects of ecDNA biology and for developing new preclinical immunocompetent mouse models of human cancers harbouring specific focal gene amplifications. |  |\n| Engineering cancer-associated genetic lesions in cells and in model |  | from the fragmentation and subsequent circularization of segments of |\n| organisms is essential to defining their contribution to tumour initiation |  | chromosomes3,4. These large (0.5–3.0 Mbp) extrachromosomal DNAs |\n| and progression and to the development of accurate preclinical models |  | (ecDNAs) are also known as ‘double minutes’ owing to their paired |\n| of human cancers. Over the past few decades, advancesin germline and |  | appearance in metaphase spreads5 (reviewed in refs. 2,6,7). ecDNAs |\n| somatic gene editing methods have substantially improved our ability |  | have been detected in several cancer types and are associated with |\n| tomodela wide range of loss-and gain-of-function mutations ina tem- |  | unfavourable prognosis8,9. At least two dozen oncogenes have been |\n| porally and spatially controlled fashion. However, focal amplifications— |  | reported in circular amplicons, with mouse double minute 2 (MDM2) |\n| a common mechanism of oncogene activation inhuman cancers1—have |  | and cellular myelocytomatosis (MYC) among the most common8. |\n| so far resisted efforts to model them in primary cells orin vivo. Although |  | A distinguishing feature of ecDNAsis the absence of centromeres, which |\n| approaches relying on the ectopic expression of individual oncogenes |  | results in their random segregation at mitosis10–12. This enables rapid |\n| by means of transgenes are useful for modelling transcriptional activa- |  | accumulation of large numbers of ecDNAs, promotes intratumoural |\n| tion, they fail to reproduce the complexity, intratumoural heterogeneity |  | heterogeneity and facilitates tumour evolution8,13,14. Genes residing |\n","cbCaiaqJxTBX8QWh","https://ap.wps.com/l/cbCaiaqJxTBX8QWh","pdf",30355630,29,"English","# Introduction\n## Engineering focal ecDNA amplifications\n## Modeling Myc and Mdm2 ecDNAs\n## Tumor formation in hepatocellular carcinoma models\n# Conclusions","[{\"question\":\"What problem does the study address about oncogene amplification modeling?\",\"answer\":\"It addresses the difficulty of engineering and studying focal gene amplifications in primary cells and model organisms, which has limited accurate preclinical modeling of cancer initiation and progression.\"},{\"question\":\"How does the reported strategy control and track ecDNA-driven amplifications?\",\"answer\":\"It engineers large focal amplifications mediated by extrachromosomal DNAs in a time-controlled manner and couples ecDNA formation with selectable markers to monitor ecDNA-containing cells under different pressures.\"},{\"question\":\"What biological effects do engineered ecDNAs have in primary cells and mice?\",\"answer\":\"Engineered Myc- and Mdm2-containing ecDNAs accumulate spontaneously, promoting proliferation, immortalization, and transformation; Mdm2-containing ecDNAs also induce tumour formation in an autochthonous hepatocellular carcinoma mouse model.\"}]","Engineered extrachromosomal oncogene amplifications promote tumorigenesis | PDF",1789994949,73]