| Title: |
Aberrant inheritance of extrachromosomal DNA amplifications promotes cancer evolution |
| Authors: |
Marom, Shir; Lifshits Dayan, Inbar; Narasimha Kadali, Venkata; Giurgiu-Kraljič, Mădălina; Koifman, Gabriela; Hakeny, Karen; Chaurasia, Madhuri; Benamozig, Orlena; Nevo, Reinat; Azuri, Ido; Ryvkin, Julia; Rotkopf, Ron; Stelzer, Gil; Oniashvili, Nino; Mardoukh, Jacques; Pollock, Sarah; Iremadze, Nika; Shipony, Zohar; Kupervaser, Meital; Wigoda, Noa; Leshkowitz, Dena; Elazar, Zvulun; Berko, Esther; Henssen, Anton G.; Shoshani, Ofer |
| Publisher Information: |
Cold Spring Harbor Laboratory Press |
| Publication Year: |
2025 |
| Collection: |
Max-Delbrueck-Center for Molecular Medicine, Berlin: MDC Repository |
| Subject Terms: |
Cancer Research; Topic 2: Molecular Processes and Therapies |
| Description: |
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. |
| Document Type: |
report |
| File Description: |
application/pdf |
| Language: |
English |
| Relation: |
https://edoc.mdc-berlin.de/id/eprint/25737/1/25737oa.pdf; Aberrant inheritance of extrachromosomal DNA amplifications promotes cancer evolution. Marom, Shir, Lifshits Dayan, Inbar, Narasimha Kadali, Venkata, Giurgiu-Kraljič, Mădălina, Koifman, Gabriela, Hakeny, Karen, Chaurasia, Madhuri, Benamozig, Orlena, Nevo, Reinat, Azuri, Ido, Ryvkin, Julia, Rotkopf, Ron, Stelzer, Gil, Oniashvili, Nino, Mardoukh, Jacques, Pollock, Sarah, Iremadze, Nika, Shipony, Zohar, Kupervaser, Meital, Wigoda, Noa, Leshkowitz, Dena, Elazar, Zvulun, Berko, Esther, Henssen, Anton G. and Shoshani, Ofer bioRxiv : 2025.09.19.677276. 21 September 2025; bioRxiv:2025.09.19.677276; https://doi.org/10.1101/2025.09.19.677276 |
| DOI: |
10.1101/2025.09.19.677276 |
| Availability: |
https://edoc.mdc-berlin.de/id/eprint/25737/; https://edoc.mdc-berlin.de/25737/; https://doi.org/10.1101/2025.09.19.677276 |
| Rights: |
cc_by_nc_nd_4 |
| Accession Number: |
edsbas.9939C3D1 |
| Database: |
BASE |