TY - JOUR
T1 - Aberrant inheritance of extrachromosomal DNA amplifications promotes cancer evolution
AU - Marom, Shir
AU - Lifshits Dayan, Inbar
AU - Narasimha Kadali, Venkata
AU - Giurgiu-Kraljič, Mădălina
AU - Koifman, Gabriela
AU - Hakeny, Karen
AU - Chaurasia, Madhuri
AU - Benamozig, Orléna
AU - Nevo, Reinat
AU - Azuri, Ido
AU - Ryvkin, Julia
AU - Rotkopf, Ron
AU - Stelzer, Gil
AU - Oniashvili, Nino
AU - Mardoukh, Jacques
AU - Pollock, Sarah
AU - Iremadze, Nika
AU - Shipony, Zohar
AU - Kupervaser, Meital
AU - Wigoda, Noa
AU - Leshkowitz, Dena
AU - Elazar, Zvulun
AU - Berko, Esther
AU - Henssen, Anton G.
AU - Shoshani, Ofer
PY - 2025/9/21
Y1 - 2025/9/21
N2 - Gene amplification in the form of extrachromosomal DNA (ecDNA) is a frequent driver in multiple cancer types. As ecDNA lack centromeres, their mitotic segregation does not follow traditional inheritance principles. However, the mechanisms that govern ecDNA fate following mitosis remain unclear. We found that ecDNA undergo numerical and structural optimization under increased selective pressure, with mitotic chromosomal tethering, or detachment, dictating ecDNA fate. When tethered, ecDNA aggregates promote uneven distribution into the newly formed daughter cells, thereby driving inter-cellular numerical heterogeneity and rapid increase of amplification under selective pressure. Mitotically detached ecDNA frequently encapsulate within micronuclei of variable size and content that appear to be highly fragile. Strikingly, ecDNA enclosed in very small micronuclei, which we term nanonuclei, are being actively degraded through autophagy. Together with ongoing structural rearrangements, nanonuclear ecDNA degradation promotes their structural evolution, which facilitates cancer cell adaptation. Our work highlights ecDNA aggregation, micronucleation, and degradation, as pivotal events in directing cancer genome evolution trajectories.Competing Interest StatementA.G.H. is a founder and stock holder in Econic Biosciences. The other authors declare no competing interests.Israel Science Foundation, 686/22Israel Cancer Research FundMinerva Stiftung, 146552
AB - Gene amplification in the form of extrachromosomal DNA (ecDNA) is a frequent driver in multiple cancer types. As ecDNA lack centromeres, their mitotic segregation does not follow traditional inheritance principles. However, the mechanisms that govern ecDNA fate following mitosis remain unclear. We found that ecDNA undergo numerical and structural optimization under increased selective pressure, with mitotic chromosomal tethering, or detachment, dictating ecDNA fate. When tethered, ecDNA aggregates promote uneven distribution into the newly formed daughter cells, thereby driving inter-cellular numerical heterogeneity and rapid increase of amplification under selective pressure. Mitotically detached ecDNA frequently encapsulate within micronuclei of variable size and content that appear to be highly fragile. Strikingly, ecDNA enclosed in very small micronuclei, which we term nanonuclei, are being actively degraded through autophagy. Together with ongoing structural rearrangements, nanonuclear ecDNA degradation promotes their structural evolution, which facilitates cancer cell adaptation. Our work highlights ecDNA aggregation, micronucleation, and degradation, as pivotal events in directing cancer genome evolution trajectories.Competing Interest StatementA.G.H. is a founder and stock holder in Econic Biosciences. The other authors declare no competing interests.Israel Science Foundation, 686/22Israel Cancer Research FundMinerva Stiftung, 146552
U2 - 10.1101/2025.09.19.677276
DO - 10.1101/2025.09.19.677276
M3 - Article
SN - 2692-8205
JO - BioRxiv
JF - BioRxiv
ER -