Engineered extrachromosomal oncogene amplifications promote tumorigenesis
Focal gene amplifications are among the most common cancer-associated mutations<sup>1</sup> 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)<sup>2</sup> 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.
Authors
- Bhargavi Dameracharla (ORCID: https://orcid.org/0000-0001-5001-5057)
- Minsi Zhang (ORCID: https://orcid.org/0009-0003-6182-1195)
- Zhengqiao Zhao (ORCID: https://orcid.org/0000-0001-6873-6098)
- Vineet Bafna (ORCID: https://orcid.org/0000-0002-5810-6241)
- Andrea Ventura (ORCID: https://orcid.org/0000-0003-4320-9907)
- Howard Y. Chang (ORCID: https://orcid.org/0000-0002-9459-4393)
- Paul S. Mischel (ORCID: https://orcid.org/0000-0002-4560-2211)
- Chiara Mastroleo
- Carlie Sigel (ORCID: https://orcid.org/0000-0001-6276-3968)
- Ylenia Cendón (ORCID: https://orcid.org/0000-0001-7525-7407)
- Katarzyna M. Głuchowska
- Jens Luebeck (ORCID: https://orcid.org/0000-0003-4391-979X)
- Yuri Pritykin
- Eric G. Sun (ORCID: https://orcid.org/0000-0002-9109-1969)
- Melissa A. Yao (ORCID: https://orcid.org/0000-0002-2274-6925)
- Davide Pradella (ORCID: https://orcid.org/0000-0002-8649-7817)
- Tanmay Mishra (ORCID: https://orcid.org/0009-0009-9658-1535)
- Gaspare La Rocca (ORCID: https://orcid.org/0000-0003-1277-0566)
- Moritz Weigl (ORCID: https://orcid.org/0000-0002-3941-5671)
- Felix Grimm (ORCID: https://orcid.org/0000-0002-2685-1167)
- Cristina R. Antonescu (ORCID: https://orcid.org/0000-0002-9717-8205)
- Marta Lisi
- Kevin Chen (ORCID: https://orcid.org/0000-0002-0674-1411)
- Shu Xin Zhang (ORCID: https://orcid.org/0000-0003-2543-5943)
- Rui Gao (ORCID: https://orcid.org/0000-0001-9835-1826)
- Hieu H. M. Nguyen (ORCID: https://orcid.org/0000-0001-9195-1757)
- Ziqi Jiao
- Mateusz M. Ozimek
- Andrea Alice Zolli
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Howard Hughes Medical Institute (US)
- Princeton University (US)
- Cornell University (US)
- University of California San Diego (US)
- Tri-Institutional PhD Program in Chemical Biology (US)
- Rockefeller University (US)
- Stanford University (US)
Publication Details
- Journal
- Nature
- Published
- 2024-12-18
- DOI
- https://doi.org/10.1038/s41586-024-08318-8
- Citations
- 25
- Primary Topic
- CRISPR and Genetic Engineering
- Type
- article
- Field-Weighted Citation Impact
- 5.85