Peer-reviewedCC BY-NC-NDNature Genetics
Micronuclear ecDNA constrains tumor cell fitness and is associated with favorable patient survival
30 affiliations
- 1Department of Pediatric Oncology/Hematology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- 2Experimental and Clinical Research Center (ECRC) of the MDC and Charité Berlin, Berlin, Germany
- 3Max Delbrück Center for Molecular Medicine, Berlin, Germany
- 4Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA
- 5Sarafan ChEM-H, Stanford University, Stanford, CA, USA
- 6Group of Theoretical Biology, The State Key Laboratory of Bio-control, School of Life Sciences, Sun Yat-sen University, Guangzhou, People's Republic of China
- 7Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- 8Oncode Institute and Princess Máxima Center for Pediatric Oncology, Utrecht, The Netherlands
- 9Department of Neurosurgery, School of Medicine, Yale University, New Haven, CT, USA
- 10Institute of Molecular Biology, Mainz, Germany
- 11Institute of Pathology, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany
- 12Experimental Pharmacology and Oncology (EPO), Berlin, Germany
- 13Advanced Light Microscopy, Max Delbrück Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Straße 10, Berlin, Germany
- 14Econic Biosciences, London, United Kingdom
- 15Department of Biochemistry, University of Utah, Salt Lake City, UT, USA
- 16Department of Clinical Neurosciences and NIHR Biomedical Research Centre, University of Cambridge, Cambridge, UK
- 17Department of Molecular Neuroscience, Transylvanian Institute of Neuroscience, Cluj-Napoca, Romania
- 18UK Dementia Research Institute, University of Cambridge, Cambridge, UK
- 19Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, Cologne, Germany
- 20Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany
- 21Department of Computer Science and Engineering, University of San Diego, San Diego, CA, USA
- 22Department of Neurosurgery, Amsterdam University Medical Centers/VUmc, Amsterdam, the Netherlands
- 23Salk Institute for Biological Studies, San Diego, CA, USA
- 24Center for Epigenetics Research, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- 25Institute of Biology, Humboldt-Universität zu Berlin, Berlin, Germany
- 26Department of Mathematics, Queen Mary University of London, London, UK
- 27Evolutionary Dynamics Group, Centre for Cancer Evolution, Barts Cancer Institute, Queen Mary University of London, London, UK
- 28Departments of Dermatology, Genetics, and Pathology, Stanford University School of Medicine, Stanford, CA, USA
- 29Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA. [email protected]
- 30Sarafan ChEM-H, Stanford University, Stanford, CA, USA. [email protected]
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.
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BibTeX
@article{bruckner2026micronuclear,
title = {{Micronuclear ecDNA constrains tumor cell fitness and is associated with favorable patient survival}},
author = {Lotte Brückner and Robin Xu and Jun Tang and Aditi Gnanasekar and Alexander Herrmann and Ivy Tsz-Lo Wong and Shu Zhang and Fengyu Tu and Madison Pilon and Alexander Kukalev and Katharina Pardon and Olga Alexandra Sidorova and Joshua Atta and Qinghao Yu and Giulia Montuori and Davide Pradella and Mila Ilić and Kentaro Suina and Marco Novais-Cruz and Sarah Kaltenbach and Denise Treue and Mădălina Giurgiu and Sergej Herzog and Ann-Sophie Hollinger and Nadine Wittstruck and Martina Fernandez and Nicole Wolozyn and Finnja Becker and Varvara-Rigina Louma and Xiaowei Yan and Rachel Schmargon and Jan R. Dörr and David Gamlin and Annika Lehmann and Dennis Gürgen and Matthias Richter and Frank P. B. Dubois and Fabrizio Simeoni and Betheney R. Pennycook and Alastair Hamilton and Ralph K. Lindemann and Courtney Dawes and Gabriel Balmus and Barbara Hero and Matthias Fischer and Vineet Bafna and Roel G.W. Verhaak and Geoffrey M. Wahl and Yang Liu and Richard P. Koche and Stamatis Papathanasiou and René Medema and Bastiaan Spanjaard and Andrea Ventura and Ana Pombo and Weini Huang and Monika Scheer and Benjamin Werner and Howard Y. Chang and Paul S. Mischel},
journal = {Nature Genetics},
year = {2026},
month = oct,
doi = {10.1038/s41588-026-02782-w},
url = {https://doi.org/10.1038/s41588-026-02782-w},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Micronuclear ecDNA constrains tumor cell fitness and is associated with favorable patient survival
AU - Lotte Brückner
AU - Robin Xu
AU - Jun Tang
AU - Aditi Gnanasekar
AU - Alexander Herrmann
AU - Ivy Tsz-Lo Wong
AU - Shu Zhang
AU - Fengyu Tu
AU - Madison Pilon
AU - Alexander Kukalev
AU - Katharina Pardon
AU - Olga Alexandra Sidorova
AU - Joshua Atta
AU - Qinghao Yu
AU - Giulia Montuori
AU - Davide Pradella
AU - Mila Ilić
AU - Kentaro Suina
AU - Marco Novais-Cruz
AU - Sarah Kaltenbach
AU - Denise Treue
AU - Mădălina Giurgiu
AU - Sergej Herzog
AU - Ann-Sophie Hollinger
AU - Nadine Wittstruck
AU - Martina Fernandez
AU - Nicole Wolozyn
AU - Finnja Becker
AU - Varvara-Rigina Louma
AU - Xiaowei Yan
AU - Rachel Schmargon
AU - Jan R. Dörr
AU - David Gamlin
AU - Annika Lehmann
AU - Dennis Gürgen
AU - Matthias Richter
AU - Frank P. B. Dubois
AU - Fabrizio Simeoni
AU - Betheney R. Pennycook
AU - Alastair Hamilton
AU - Ralph K. Lindemann
AU - Courtney Dawes
AU - Gabriel Balmus
AU - Barbara Hero
AU - Matthias Fischer
AU - Vineet Bafna
AU - Roel G.W. Verhaak
AU - Geoffrey M. Wahl
AU - Yang Liu
AU - Richard P. Koche
AU - Stamatis Papathanasiou
AU - René Medema
AU - Bastiaan Spanjaard
AU - Andrea Ventura
AU - Ana Pombo
AU - Weini Huang
AU - Monika Scheer
AU - Benjamin Werner
AU - Howard Y. Chang
AU - Paul S. Mischel
PY - 2026
DA - 2026/10/12
JO - Nature Genetics
DO - 10.1038/s41588-026-02782-w
UR - https://doi.org/10.1038/s41588-026-02782-w
AB - 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.
SN - 1061-4036
SN - 1546-1718
ER -