{ "abstract": "Extrachromosomal DNA (ecDNA) contributes to cancer genome instability by enabling high-copy oncogene amplification, intratumoural heterogeneity and rapid genetic change. Micronuclei (MN) are frequently observed in chromosomally unstable cancers, yet their origins and relevance in ecDNA-driven tumours remain incompletely understood. Here, we investigate the relationship between ecDNA segregation errors and MN formation. We find that ecDNA frequently localizes to MN and represents a prominent source of MN content in ecDNA-positive cancer cells. Mitotic clustering of oncogene-bearing ecDNAs is associated with asymmetric inheritance and mis-segregation into MN. Transfer of oncogenes from ecDNA into MN is accompanied by reduced transcriptional output. Single-MN sequencing shows that individual MN are enriched for ecDNA to a degree that exceeds expectations from stochastic mis-segregation and that in MN oncogenes originating from multiple distinct ecDNAs coalesce. Using live-cell imaging, we observe that cells inheriting ecDNA-positive MN show limited proliferative capacity and an increased likelihood of cell death. In neuroblastoma patients with MYCN -amplified ecDNA, higher frequencies of ecDNA-positive MN at diagnosis are associated with improved event-free and overall survival. Together, these findings link ecDNA mis-segregation to MN formation and reduced cellular fitness, suggesting that ecDNA-positive MN may reflect a state of impaired oncogenic ecDNA function with potential relevance for clinical outcome.", "abstract_shown": true, "affiliations": [ "Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany", "Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin, Berlin, Germany", "Max Delbrück Center for Molecular Medicine, Berlin, Germany", "Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA", "Sarafan ChEM-H, Stanford University, Stanford, CA, USA", "Group of Theoretical Biology, The State Key Laboratory of Bio-control, School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China", "Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA", "Oncode Institute and Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands", "Department of Neurosurgery, School of Medicine, Yale University, New Haven, CT, USA", "Institute of Molecular Biology, Mainz, Germany", "Institute of Pathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany", "Experimental Pharmacology and Oncology (EPO), Berlin, Germany", "Advanced Light Microscopy, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Straße 10, Berlin, Germany", "Econic Biosciences, London, United Kingdom", "Department of Biochemistry, University of Utah, Salt Lake City, UT, USA", "Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK", "Department of Molecular Neuroscience, Transylvanian Institute of Neuroscience, Cluj-Napoca, Romania", "UK Dementia Research Institute, University of Cambridge, Cambridge, UK", "Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, Cologne, Germany", "Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany", "Department of Computer Science and Engineering, University of San Diego, San Diego, CA, USA", "Department of Neurosurgery, Amsterdam University Medical Centers/VUmc, Amsterdam, the Netherlands", "Salk Institute for Biological Studies, San Diego, CA, USA", "Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA", "Institute of Biology, Humboldt-Universität zu Berlin, Berlin, Germany", "Department of Mathematics, Queen Mary University of London, London, UK", "Evolutionary Dynamics Group, Centre for Cancer Evolution, Barts Cancer Institute, Queen Mary University of London, London, UK", "Departments of Dermatology, Genetics, and Pathology, Stanford University School of Medicine, Stanford, CA, USA", "Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. pmischel@stanford.edu", "Sarafan ChEM-H, Stanford University, Stanford, CA, USA. pmischel@stanford.edu" ], "article_type": null, "arxiv": null, "author_total": 61, "authors": [ { "affs": [ 0, 1, 2 ], "name": "Lotte Brückner", "orcid": "0000-0002-6155-2277" }, { "affs": [ 0, 1 ], "name": "Robin Xu", "orcid": "0000-0002-5618-246X" }, { "affs": [ 3, 4 ], "name": "Jun Tang", "orcid": "0009-0004-4606-2458" }, { "affs": [ 3, 4 ], "name": "Aditi Gnanasekar", "orcid": "0000-0002-8303-8674" }, { "affs": [ 0 ], "name": "Alexander Herrmann", "orcid": "0000-0002-2749-9003" }, { "affs": [ 3, 4 ], "name": "Ivy Tsz-Lo Wong", "orcid": "0000-0002-9761-3422" }, { "affs": [ 3, 4 ], "name": "Shu Zhang", "orcid": "0000-0003-2543-5943" }, { "affs": [ 5 ], "name": "Fengyu Tu", "orcid": "0000-0001-8748-7250" }, { "affs": [ 0 ], "name": "Madison Pilon", "orcid": "0000-0001-9060-4817" }, { "affs": [ 2 ], "name": "Alexander Kukalev", "orcid": "0000-0001-5847-3773" }, { "affs": [ 0, 1 ], "name": "Katharina Pardon", "orcid": "0009-0001-5048-3261" }, { "affs": [ 0, 1 ], "name": "Olga Alexandra Sidorova", "orcid": "0009-0004-1459-1662" }, { "affs": [ 0, 1 ], "name": "Joshua Atta" }, { "affs": [ 0, 1 ], "name": "Qinghao Yu", "orcid": "0000-0002-2151-9624" }, { "affs": [ 0, 1 ], "name": "Giulia Montuori", "orcid": "0009-0007-9072-7156" }, { "affs": [ 6 ], "name": "Davide Pradella", "orcid": "0000-0002-8649-7817" }, { "affs": [ 7 ], "name": "Mila Ilić", "orcid": "0000-0003-4664-9393" }, { "affs": [ 8 ], "name": "Kentaro Suina", "orcid": "0000-0001-7805-5480" }, { "affs": [ 7 ], "name": "Marco Novais-Cruz", "orcid": "0000-0002-0361-4855" }, { "affs": [ 9 ], "name": "Sarah Kaltenbach" }, { "affs": [ 10 ], "name": "Denise Treue", "orcid": "0000-0002-0657-5505" }, { "affs": [ 0, 1 ], "name": "Mădălina Giurgiu", "orcid": "0000-0001-5007-7442" }, { "affs": [ 2 ], "name": "Sergej Herzog" }, { "affs": [ 0, 1 ], "name": "Ann-Sophie Hollinger" }, { "affs": [ 0, 1 ], "name": "Nadine Wittstruck", "orcid": "0009-0000-4378-3226" }, { "affs": [ 0, 1 ], "name": "Martina Fernandez" }, { "affs": [ 0 ], "name": "Nicole Wolozyn" }, { "affs": [ 0, 1 ], "name": "Finnja Becker", "orcid": "0009-0003-7014-7307" }, { "affs": [ 0, 1 ], "name": "Varvara-Rigina Louma" }, { "affs": [ 3, 4 ], "name": "Xiaowei Yan", "orcid": "0000-0002-4846-8812" }, { "affs": [ 0, 1 ], "name": "Rachel Schmargon", "orcid": "0009-0009-3535-7185" }, { "affs": [ 0, 1 ], "name": "Jan R. Dörr", "orcid": "0000-0002-4927-6548" }, { "affs": [ 0, 1 ], "name": "David Gamlin" }, { "affs": [ 10 ], "name": "Annika Lehmann" }, { "affs": [ 11 ], "name": "Dennis Gürgen", "orcid": "0000-0001-9241-6537" }, { "affs": [ 12 ], "name": "Matthias Richter", "orcid": "0000-0002-5339-0781" }, { "affs": [ 10 ], "name": "Frank P. B. Dubois", "orcid": "0000-0002-7654-6208" }, { "affs": [ 13 ], "name": "Fabrizio Simeoni", "orcid": "0000-0002-5543-6413" }, { "affs": [ 13 ], "name": "Betheney R. Pennycook", "orcid": "0000-0001-5721-6994" }, { "affs": [ 13 ], "name": "Alastair Hamilton", "orcid": "0000-0001-7242-0221" }, { "affs": [ 13 ], "name": "Ralph K. Lindemann", "orcid": "0000-0003-2399-3992" }, { "affs": [ 14 ], "name": "Courtney Dawes", "orcid": "0009-0006-3047-5762" }, { "affs": [ 15, 16, 17 ], "name": "Gabriel Balmus", "orcid": "0000-0003-2872-4468" }, { "affs": [ 18 ], "name": "Barbara Hero", "orcid": "0000-0003-4129-890X" }, { "affs": [ 19, 18 ], "name": "Matthias Fischer", "orcid": "0000-0003-1363-1242" }, { "affs": [ 20 ], "name": "Vineet Bafna", "orcid": "0000-0002-5810-6241" }, { "affs": [ 21, 8 ], "name": "Roel G.W. Verhaak", "orcid": "0000-0003-2773-0436" }, { "affs": [ 22 ], "name": "Geoffrey M. Wahl", "orcid": "0000-0003-3658-2279" }, { "affs": [ 14 ], "name": "Yang Liu", "orcid": "0000-0002-3889-9707" }, { "affs": [ 23 ], "name": "Richard P. Koche", "orcid": "0000-0002-6820-5083" }, { "affs": [ 9 ], "name": "Stamatis Papathanasiou", "orcid": "0000-0001-6969-044X" }, { "affs": [ 7 ], "name": "René Medema" }, { "affs": [ 0, 1 ], "name": "Bastiaan Spanjaard", "orcid": "0000-0003-1309-8839" }, { "affs": [ 6 ], "name": "Andrea Ventura", "orcid": "0000-0003-4320-9907" }, { "affs": [ 24, 2 ], "name": "Ana Pombo", "orcid": "0000-0002-7493-6288" }, { "affs": [ 25 ], "name": "Weini Huang", "orcid": "0000-0002-9016-2665" }, { "affs": [ 0 ], "name": "Monika Scheer", "orcid": "0000-0002-0665-6268" }, { "affs": [ 26 ], "name": "Benjamin Werner", "orcid": "0000-0002-6857-8699" }, { "affs": [ 27 ], "name": "Howard Y. Chang", "orcid": "0000-0002-9459-4393" }, { "affs": [ 28, 29 ], "name": "Paul S. Mischel", "orcid": "0000-0002-4560-2211" } ], "bibtex": "https://research.draconitic.com/paper/4qwqv1qm6m20w.bib", "cited_by": 9, "doi": "10.1038/s41588-026-02782-w", "fulltext_url": null, "id": "4qwqv1qm6m20w", "issns": [ "1061-4036", "1546-1718" ], "landing_url": "https://doi.org/10.1038/s41588-026-02782-w", "language": "en", "licence": "CC-BY-NC-ND", "licence_label": "CC BY-NC-ND", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1307|Microtubule and mitosis dynamics" ], [ "openalex", "1311|Genomic variations and chromosomal abnormalities" ] ], "openalex": "W7221567413", "pdf_url": "https://www.nature.com/articles/s41588-026-02782-w.pdf", "pmcid": "PMC12047879", "pmid": "40321211", "published": "2026-10-12", "publisher": "Nature Portfolio", "ris": "https://research.draconitic.com/paper/4qwqv1qm6m20w.ris", "sources": [ { "first_seen": "2026-11-04T13:21:07Z", "native_id": "W7221567413", "source": "openalex", "url": "https://doi.org/10.1038/s41588-026-02782-w" } ], "subjects": [ { "field": "biology", "origin": "openalex:1307|Microtubule and mitosis dynamics", "subfield": "cell-biology" }, { "field": "biology", "origin": "openalex:1311|Genomic variations and chromosomal abnormalities", "subfield": "genetics-genomics" } ], "title": "Micronuclear ecDNA constrains tumor cell fitness and is associated with favorable patient survival", "title_text": "Micronuclear ecDNA constrains tumor cell fitness and is associated with favorable patient survival", "type": "peer-reviewed", "updated_at": "2026-11-09T13:21:07Z", "url": "https://research.draconitic.com/paper/4qwqv1qm6m20w", "venue": "Nature Genetics", "versions": [] }