Micronuclear ecDNA constrains tumor cell fitness and is associated with favorable patient survival
Year: 2026
Type: article
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.
Source: Nature Genetics
Authors: Lotte Brückner, Robin Xu, Jun Tang, Aditi Gnanasekar, Alexander Herrmann, Ivy Tsz-Lo Wong, Shu Zhang, Fengyu Tu, Madison Pilon, Alexander Kukalev, Katharina Pardon, Olga Sidorova, Joshua Atta, Qinghao Yu, Giulia Montuori, Davide Pradella, Mila Ilić, Kentaro Suina, Marco Novais-Cruz, Sarah Kaltenbach, Denise Treue, Mădălina Giurgiu-Kraljič, Sergej Herzog, Ann-Sophie Hollinger, Nadine Wittstruck, Martina Fernandez, Nicole Wolozyn, Finnja Becker, Varvara-Rigina Louma, Xiaowei Yan, Rachel Schmargon, Jan R. Dörr, David Gamlin, Annika Lehmann, Dennis Gürgen, Matthias Richter, Frank Dubois, Fabrizio Simeoni, Betheney R. Pennycook, Alastair Hamilton, Ralph K. Lindemann, Courtney Dawes, Gabriel Balmus, Barbara Hero, Matthias Fischer, Vineet Bafna, Roel Verhaak, Geoffrey Wahl, Yang Liu, Richard P. Koche, Stamatis Papathanasiou, René Medema, Bastiaan Spanjaard, Andrea Ventura, Ana Pombo, Weini Huang, Monika Scheer, Benjamin Werner, Howard Y. Chang, Paul S. Mischel, Anton G. Henssen
Institutions: Max Delbrück Center, Charité – Universitätsmedizin Berlin, Stanford Medicine, Stanford University, Sun Yat-sen University, Memorial Sloan Kettering Cancer Center, Oncode Institute, Princess Máxima Center, Yale University, Institute of Molecular Biology, Humboldt-Universität zu Berlin, University of Utah, University of Cambridge, UK Dementia Research Institute, NIHR Cambridge Biomedical Research Centre, Transylvanian Institute of Neuroscience, University of Cologne, University Hospital Cologne, University of San Diego, Amsterdam University Medical Centers, Amsterdam UMC Location Vrije Universiteit Amsterdam, Salk Institute for Biological Studies, Queen Mary University of London, Barts Cancer Institute, German Cancer Research Center, Deutsches Konsortium für Translationale Krebsforschung
Language: English
Subfield: Cell Biology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: CHDI Foundation, Memorial Sloan-Kettering Cancer Center, UK Research and Innovation, Mark Foundation For Cancer Research, Barts Charity, Cancer Research UK, European Commission, Deutsche Forschungsgemeinschaft, National Natural Science Foundation of China, Associazione Italiana per la Ricerca sul Cancro, Deutsche Krebshilfe, Stiftung Charité, Berlin Institute of Health, UK Dementia Research Institute, National Institutes of Health, Medical Research Council, National Cancer Institute, NextGenerationEU
Awards: Smart Objects For Intelligent Applications, G1588214524, G1796198730, eDyNAmiC - CHARITE, G2007345164, G2051006376, G2162712764, GRK 2424: Computermethoden für personalisierte Therapien in der Onkologie, G245757704, G289723095, eDyNAmiC-QMUL, eDyNAmiC - UCSD, G394081560, eDyNAmiC - STANFORD, SFB 1588: Entschlüsselung evolutionärer Mechanismen beim Neuroblastom, Quantifying the evolutionary dynamics of extra-chromosomal DNA in human cancers., G4238938849, G4268089617, G434337789, G4830400555, G5467192712, G5594779030, G6393038893, G6843509793, G7745828677, G7796364618, eDyNAmiC (extrachromosomal DNA in Cancer) - Understanding the biology of ecDNA generation and action, and developing new ways to target these mechanisms in cancer, G8393059803, G8687509801, Sequenzspezifische DNA Rekombination als Ursache genomischer Mutationen im Neuroblastom, Cancer Center Support Grant, Investigating the roles of oncogenic extrachromosomal circular DNAs in cancer
OpenAlex ID: W7221567413