Coordinated inheritance of extrachromosomal DNAs in cancer cells

King L. Hung, Matthew G. Jones, Ivy Tsz-Lo Wong, Ellis J. Curtis, Joshua T. Lange, Britney Jiayu He, Jens Luebeck, Rachel Schmargon, Elisa Scanu, Lotte Brückner, Xiaowei Yan, Rui Li, Aditi Gnanasekar, Rocío Chamorro González, Julia A. Belk, Zhonglin Liu, Bruno Melillo, Vineet Bafna, Jan R. Dörr, Benjamin Werner, Weini Huang, Benjamin F. Cravatt, Anton G. Henssen, Paul S. Mischel () and Howard Y. Chang ()
Additional contact information
King L. Hung: Stanford University
Matthew G. Jones: Stanford University
Ivy Tsz-Lo Wong: Stanford University
Ellis J. Curtis: Stanford University
Joshua T. Lange: Stanford University
Britney Jiayu He: Stanford University
Jens Luebeck: University of California at San Diego
Rachel Schmargon: Max Delbrück Center for Molecular Medicine and Charité—Universitätsmedizin Berlin
Elisa Scanu: Queen Mary University of London
Lotte Brückner: Max Delbrück Center for Molecular Medicine and Charité—Universitätsmedizin Berlin
Xiaowei Yan: Stanford University
Rui Li: Stanford University
Aditi Gnanasekar: Stanford University
Rocío Chamorro González: Max Delbrück Center for Molecular Medicine and Charité—Universitätsmedizin Berlin
Julia A. Belk: Stanford University
Zhonglin Liu: Scripps Research
Bruno Melillo: Scripps Research
Vineet Bafna: University of California at San Diego
Jan R. Dörr: Max Delbrück Center for Molecular Medicine and Charité—Universitätsmedizin Berlin
Benjamin Werner: Queen Mary University of London
Weini Huang: Queen Mary University of London
Benjamin F. Cravatt: Scripps Research
Anton G. Henssen: Max Delbrück Center for Molecular Medicine and Charité—Universitätsmedizin Berlin
Paul S. Mischel: Stanford University
Howard Y. Chang: Stanford University

Nature, 2024, vol. 635, issue 8037, 201-209

Abstract: Abstract The chromosomal theory of inheritance dictates that genes on the same chromosome segregate together while genes on different chromosomes assort independently1. Extrachromosomal DNAs (ecDNAs) are common in cancer and drive oncogene amplification, dysregulated gene expression and intratumoural heterogeneity through random segregation during cell division2,3. Distinct ecDNA sequences, termed ecDNA species, can co-exist to facilitate intermolecular cooperation in cancer cells4. How multiple ecDNA species within a tumour cell are assorted and maintained across somatic cell generations is unclear. Here we show that cooperative ecDNA species are coordinately inherited through mitotic co-segregation. Imaging and single-cell analyses show that multiple ecDNAs encoding distinct oncogenes co-occur and are correlated in copy number in human cancer cells. ecDNA species are coordinately segregated asymmetrically during mitosis, resulting in daughter cells with simultaneous copy-number gains in multiple ecDNA species before any selection. Intermolecular proximity and active transcription at the start of mitosis facilitate the coordinated segregation of ecDNA species, and transcription inhibition reduces co-segregation. Computational modelling reveals the quantitative principles of ecDNA co-segregation and co-selection, predicting their observed distributions in cancer cells. Coordinated inheritance of ecDNAs enables co-amplification of specialized ecDNAs containing only enhancer elements and guides therapeutic strategies to jointly deplete cooperating ecDNA oncogenes. Coordinated inheritance of ecDNAs confers stability to oncogene cooperation and novel gene regulatory circuits, allowing winning combinations of epigenetic states to be transmitted across cell generations.

Date: 2024
References: Add references at CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41586-024-07861-8 Abstract (text/html)
Access to the full text of the articles in this series is restricted.

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:nature:v:635:y:2024:i:8037:d:10.1038_s41586-024-07861-8

Ordering information: This journal article can be ordered from
https://www.nature.com/

DOI: 10.1038/s41586-024-07861-8

Access Statistics for this article

Nature is currently edited by Magdalena Skipper

More articles in Nature from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().