Engineered extrachromosomal oncogene amplifications promote tumorigenesis

• 成果类型: Article
• 署名作者: Pradella, Davide; Zhang, Minsi; Gao, Rui; Yao, Melissa A.; Gluchowska, Katarzyna M.; Cendon-Florez, Ylenia; Mishra, Tanmay; La Rocca, Gaspare; Weigl, Moritz; Jiao, Ziqi; Nguyen, Hieu H. M.; Lisi, Marta; Ozimek, Mateusz M.; Mastroleo, Chiara; Chen, Kevin; Grimm, Felix; Luebeck, Jens; Zhang, Shu; Zolli, Andrea Alice; Sun, Eric G.; Dameracharla, Bhargavi; Zhao, Zhengqiao; Pritykin, Yuri; Sigel, Carlie; Chang, Howard Y.; Mischel, Paul S.; Bafna, Vineet; Antonescu, Cristina R.; Ventura, Andrea
• 署名单位: Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; Cornell University; Weill Cornell Medicine; Memorial Sloan Kettering Cancer Center; Memorial Sloan Kettering Cancer Center; University of California System; University of California San Diego; Stanford University; Stanford University; Stanford University; Stanford University; Memorial Sloan Kettering Cancer Center; Rockefeller University; Cornell University; Weill Cornell Medicine; Princeton University; Princeton University; Memorial Sloan Kettering Cancer Center; Howard Hughes Medical Institute; Stanford University; University of California System; University of California San Diego
• 刊物名称: Nature
• ISSN/ISSBN: 0028-3454
• DOI: 10.1038/s41586-024-08318-8
• 发表日期: 2025-01-23
• 关键词: negative autoregulation; embryonic lethality; mdm2-deficient mice; gene; mdm2; dna; chromatin; p53; liposarcoma; expression

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.