Engineered extrachromosomal oncogene amplifications promote tumorigenesis

• 全文链接

工程修饰的染色体外癌基因扩增促进肿瘤发生

关键词：

来源：

nature

全文链接：

//agri.nais.net.cn/topic/downloadFile/5fd40eef-0aad-48ee-938b-949b1c6d4c8e

来源地址：

https://www.nature.com/articles/s41586-024-08318-8

资源所属：

马铃薯基因组设计育种

类型：

学术文献

语种：

中文

原文发布日期：

2024-12-18

摘要：

Focal gene amplifications are among the most common cancer-associated mutations1 but have proven challenging to engineer in primary cells and model organisms. Here we describe a general strategy to engineer large (more than 1 Mbp) focal amplifications mediated by extrachromosomal DNAs (ecDNAs)2 in a spatiotemporally controlled manner in cells and in mice. By coupling ecDNA formation with expression of selectable markers, we track the dynamics of ecDNA-containing cells under physiological conditions and in the presence of specific selective pressures. We also apply this approach to generate mice harbouring Cre-inducible Myc- and Mdm2-containing ecDNAs analogous to those occurring in human cancers. We show that the engineered ecDNAs spontaneously accumulate in primary cells derived from these animals, promoting their proliferation, immortalization and transformation. Finally, we demonstrate the ability of Mdm2-containing ecDNAs to promote tumour formation in an autochthonous mouse model of hepatocellular carcinoma. These findings offer insights into the role of ecDNA-mediated gene amplifications in tumorigenesis. We anticipate that this approach will be valuable for investigating further unresolved aspects of ecDNA biology and for developing new preclinical immunocompetent mouse models of human cancers harbouring specific focal gene amplifications.