Coordinated inheritance of extrachromosomal DNAs in cancer cells

作者：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, Howard Y. Chang · 发表于：Nature · 年份：2024 · DOI：10.1038/s41586-024-07861-8 · 被引用次数：92 · 研究领域：Cancer Genomics and Diagnostics、Epigenetics and DNA Methylation、Single-cell and spatial transcriptomics

Abstract The chromosomal theory of inheritance dictates that genes on the same chromosome segregate together while genes on different chromosomes assort independently 1 . Extrachromosomal DNAs (ecDNAs) are common in cancer and drive oncogene amplification, dysregulated gene expression and intratumoural heterogeneity through random segregation during cell division 2,3 . Distinct ecDNA sequences, termed ecDNA species, can co-exist to facilitate intermolecular cooperation in cancer cells 4 . 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 enhan...