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DOI 10.1038/s41588-026-02782-w

Медицинская библиотека · Nature genetics · 2026

Micronuclear ecDNA constrains tumor cell fitness and is associated with favorable patient survival.

Brückner Lotte, Xu Robin, Tang Jun, Gnanasekar Aditi, Herrmann Alexander, Wong Ivy Tsz-Lo, Zhang Shu, Tu Fengyu, Pilon Madison, Kukalev Alexander, Pardon Katharina, Sidorova Olga, Atta Joshua, Yu Qinghao, Montuori Giulia, Pradella Davide, Ilić Mila, Suina Kentaro, Novais-Cruz Marco, Kaltenbach Sarah, Treue Denise, Giurgiu-Kraljič Mădălina, Herzog Sergej, Hollinger Ann-Sophie, Wittstruck Nadine, Fernandez Martina, Wolozyn Nicole, Becker Finnja, Louma Varvara-Rigina, Yan Xiaowei, Schmargon Rachel, Dörr Jan R, Gamlin David, Lehmann Annika, Gürgen Dennis, Richter Matthias, Dubois Frank, Simeoni Fabrizio, Pennycook Betheney R, Hamilton Alastair, Lindemann Ralph K, Dawes Courtney, Balmus Gabriel, Hero Barbara, Fischer Matthias, Bafna Vineet, Verhaak Roel, Wahl Geoffrey, Liu Yang, Koche Richard P, Papathanasiou Stamatis, Medema René, Spanjaard Bastiaan, Ventura Andrea, Pombo Ana, Huang Weini, Scheer Monika, Werner Benjamin, Chang Howard Y, Mischel Paul S, Henssen Anton G

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Аннотация

Extrachromosomal DNA (ecDNA) contributes to cancer genome instability by enabling high-copy oncogene amplification and genetic intratumoral heterogeneity. Micronuclei (MNs) are common in chromosomally unstable cancers, yet their role in ecDNA-driven tumors remains unclear. Here we investigate how ecDNA damage, mitotic segregation and MN formation are linked. We find that ecDNAs are a major source of MNs following their damage, particularly under replication stress. Replication stress promotes mitotic ecDNA clustering, asymmetric inheritance, mis-segregation into MNs and reduced transcriptional output. Single-MN sequencing reveals that multiple distinct ecDNA species coalesce within individual MNs. Cells inheriting ecDNA+ MNs display impaired proliferative capacity and are more likely to undergo cell death. In patients with MYCN-amplified neuroblastoma, higher frequencies of ecDNA+ MNs at diagnosis are associated with improved overall survival. Together, these findings identify ecDNA mis-segregation as a mechanism that limits tumor fitness, highlighting mitotic ecDNA retention as a potential therapeutic vulnerability.

Для цитирования: Brückner Lotte, Xu Robin, Tang Jun, Gnanasekar Aditi, Herrmann Alexander, Wong Ivy Tsz-Lo, Zhang Shu, Tu Fengyu, Pilon Madison, Kukalev Alexander, Pardon Katharina, Sidorova Olga, Atta Joshua, Yu Qinghao, Montuori Giulia, Pradella Davide, Ilić Mila, Suina Kentaro, Novais-Cruz Marco, Kaltenbach Sarah, Treue Denise, Giurgiu-Kraljič Mădălina, Herzog Sergej, Hollinger Ann-Sophie, Wittstruck Nadine, Fernandez Martina, Wolozyn Nicole, Becker Finnja, Louma Varvara-Rigina, Yan Xiaowei, Schmargon Rachel, Dörr Jan R, Gamlin David, Lehmann Annika, Gürgen Dennis, Richter Matthias, Dubois Frank, Simeoni Fabrizio, Pennycook Betheney R, Hamilton Alastair, Lindemann Ralph K, Dawes Courtney, Balmus Gabriel, Hero Barbara, Fischer Matthias, Bafna Vineet, Verhaak Roel, Wahl Geoffrey, Liu Yang, Koche Richard P, Papathanasiou Stamatis, Medema René, Spanjaard Bastiaan, Ventura Andrea, Pombo Ana, Huang Weini, Scheer Monika, Werner Benjamin, Chang Howard Y, Mischel Paul S, Henssen Anton G. Micronuclear ecDNA constrains tumor cell fitness and is associated with favorable patient survival.. Nature genetics. 2026. DOI: 10.1038/s41588-026-02782-w.
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