Coordinated inheritance of extrachromosomal DNAs in cancer cells
成果类型：
Article
署名作者：
Hung, King L.; Jones, Matthew G.; Wong, Ivy Tsz-Lo; Curtis, Ellis J.; Lange, Joshua T.; He, Britney Jiayu; Luebeck, Jens; Schmargon, Rachel; Scanu, Elisa; Brueckner, Lotte; Yan, Xiaowei; Li, Rui; Gnanasekar, Aditi; Gonzalez, Rocio Chamorro; Belk, Julia A.; Liu, Zhonglin; Melillo, Bruno; Bafna, Vineet; Doerr, Jan R.; Werner, Benjamin; Huang, Weini; Cravatt, Benjamin F.; Henssen, Anton G.; Mischel, Paul S.; Chang, Howard Y.
署名单位：
Stanford University; Stanford University; Stanford University; University of California System; University of California San Diego; University of California System; University of California San Diego; Helmholtz Association; Max Delbruck Center for Molecular Medicine; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; Free University of Berlin; Humboldt University of Berlin; Charite Universitatsmedizin Berlin; University of London; Queen Mary University London; Helmholtz Association; Max Delbruck Center for Molecular Medicine; Scripps Research Institute; Harvard University; Massachusetts Institute of Technology (MIT); Broad Institute; University of London; Queen Mary University London; Sun Yat Sen University; Helmholtz Association; German Cancer Research Center (DKFZ); Humboldt University of Berlin; Free University of Berlin; Charite Universitatsmedizin Berlin; Berlin Institute of Health; Stanford University; Howard Hughes Medical Institute; Stanford University
刊物名称：
Nature
ISSN/ISSBN：
0028-5645
DOI：
10.1038/s41586-024-07861-8
发表日期：
2024-11-07
关键词：
double minute chromosomes
read alignment
amplification
transcription
elimination
gene
EVOLUTION
amplify
damage
MODEL
摘要：
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. Cooperative species of extrachromosomal DNAs are coordinately inherited through mitotic co-segregation.