美国斯坦福大学Howard Y. Chang和Paul S. Mischel共同合作，近期取得重要工作进展。他们研究提出了癌细胞染色体外DNA的协调遗传。相关研究成果2024年11月6日在线发表于《自然》杂志上。

据介绍，染色体遗传理论表明，同一染色体上的基因分离在一起，而不同染色体上的遗传基因独立组合。染色体外DNA（ecDNA）在癌症中很常见，并通过细胞分裂过程中的随机分离驱动癌基因扩增、基因表达失调和肿瘤内异质性。不同的ecDNA序列，称为ecDNA物种，可以共存以促进癌症细胞中的分子间合作。肿瘤细胞内的多种ecDNA物种是如何在体细胞世代中分类和维持的尚不清楚。

研究人员表明，合作的ecDNA物种是通过有丝分裂共分离协调遗传的。影像学和单细胞分析表明，在人类癌症细胞中，编码不同致癌基因的多个ecDNA同时出现，并且拷贝数相关。在有丝分裂过程中，ecDNA物种不对称地协调分离，导致在任何选择之前，多个ecDNA物种的子细胞同时获得拷贝数。有丝分裂开始时的分子间接近和主动转录促进了ecDNA物种的协调分离，转录抑制减少了共分离。

计算模型揭示了ecDNA共分离和共选择的定量原理，预测了它们在癌症细胞中的观察分布。ecDNA的协同遗传能够共同扩增仅含有增强子元件的特异性ecDNA，并指导治疗策略共同耗竭合作的ecDNA癌基因。ecDNA的协调遗传赋予了癌基因合作和新基因调控回路的稳定性，使表观遗传状态的组合能够在细胞世代间传播。

附：英文原文

Title: Coordinated inheritance of extrachromosomal DNAs in cancer cells

Author: 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, Brckner, Lotte, Yan, Xiaowei, Li, Rui, Gnanasekar, Aditi, Chamorro Gonzlez, Roco, Belk, Julia A., Liu, Zhonglin, Melillo, Bruno, Bafna, Vineet, Drr, Jan R., Werner, Benjamin, Huang, Weini, Cravatt, Benjamin F., Henssen, Anton G., Mischel, Paul S., Chang, Howard Y.

Issue&Volume: 2024-11-06

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.

DOI: 10.1038/s41586-024-07861-8

Source: https://www.nature.com/articles/s41586-024-07861-8