Engineered extrachromosomal oncogene amplifications promote tumorigenesis

Davide Pradella, Minsi Zhang, Rui Gao, Melissa A. Yao, Katarzyna M. Gluchowska, Ylenia Cendon-Florez, Tanmay Mishra, Gaspare La Rocca, Moritz Weigl, Ziqi Jiao, Hieu H. M. Nguyen, Marta Lisi, Mateusz M. Ozimek, Chiara Mastroleo, Kevin Chen, Felix Grimm, Jens Luebeck, Shu Zhang, Andrea Alice Zolli, Eric G. Sun, Bhargavi Dameracharla, Zhengqiao Zhao, Yuri Pritykin, Carlie Sigel, Howard Y. Chang, Paul S. Mischel, Vineet Bafna, Cristina R. Antonescu and Andrea Ventura ()
Additional contact information
Davide Pradella: Memorial Sloan Kettering Cancer Center
Minsi Zhang: Memorial Sloan Kettering Cancer Center
Rui Gao: Memorial Sloan Kettering Cancer Center
Melissa A. Yao: Memorial Sloan Kettering Cancer Center
Katarzyna M. Gluchowska: Memorial Sloan Kettering Cancer Center
Ylenia Cendon-Florez: Memorial Sloan Kettering Cancer Center
Tanmay Mishra: Memorial Sloan Kettering Cancer Center
Gaspare La Rocca: Memorial Sloan Kettering Cancer Center
Moritz Weigl: Memorial Sloan Kettering Cancer Center
Ziqi Jiao: Memorial Sloan Kettering Cancer Center
Hieu H. M. Nguyen: Memorial Sloan Kettering Cancer Center
Marta Lisi: Memorial Sloan Kettering Cancer Center
Mateusz M. Ozimek: Memorial Sloan Kettering Cancer Center
Chiara Mastroleo: Memorial Sloan Kettering Cancer Center
Kevin Chen: Memorial Sloan Kettering Cancer Center
Felix Grimm: Memorial Sloan Kettering Cancer Center
Jens Luebeck: UC San Diego
Shu Zhang: Stanford University
Andrea Alice Zolli: Memorial Sloan Kettering Cancer Center
Eric G. Sun: Memorial Sloan Kettering Cancer Center
Bhargavi Dameracharla: UC San Diego
Zhengqiao Zhao: Princeton University
Yuri Pritykin: Princeton University
Carlie Sigel: Memorial Sloan Kettering Cancer Center
Howard Y. Chang: Stanford University
Paul S. Mischel: Stanford University School of Medicine
Vineet Bafna: UC San Diego
Cristina R. Antonescu: Memorial Sloan Kettering Cancer Center
Andrea Ventura: Memorial Sloan Kettering Cancer Center

Nature, 2025, vol. 637, issue 8047, 955-964

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41586-024-08318-8

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