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Updated: Jun 4, 2025
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Testing Targeted Therapies in Cancer using Structural DNA Alteration Analysis and Patient-Derived Xenografts
Published on: July 25, 2020
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Engineered extrachromosomal oncogene amplifications promote tumorigenesis.
Davide Pradella1, Minsi Zhang1,2, Rui Gao1,3
1Cancer Biology and Genetics Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nature
|December 18, 2024
Summary
Scientists engineered large focal gene amplifications using extrachromosomal DNAs (ecDNAs) in cells and mice. This breakthrough enables studying cancer-associated mutations and developing new preclinical cancer models.
Area of Science:
- Molecular Biology
- Genetics
- Cancer Research
Background:
- Focal gene amplifications are common cancer mutations.
- Engineering these amplifications in model systems is difficult.
Purpose of the Study:
- To develop a general strategy for engineering large focal gene amplifications using extrachromosomal DNAs (ecDNAs).
- To investigate the role of ecDNA-mediated amplifications in tumorigenesis.
- To create new preclinical models for cancer research.
Main Methods:
- Engineered large focal amplifications mediated by ecDNAs in a spatiotemporally controlled manner.
- Coupled ecDNA formation with selectable markers to track ecDNA dynamics.
- Generated mice with Cre-inducible Myc- and Mdm2-containing ecDNAs.
- Demonstrated ecDNA-driven tumor formation in a mouse model.
Main Results:
- Successfully engineered large focal amplifications using ecDNAs in cells and mice.
- Observed spontaneous ecDNA accumulation in primary cells, promoting proliferation, immortalization, and transformation.
- Showed Mdm2-containing ecDNAs promote hepatocellular carcinoma formation in mice.
Conclusions:
- The developed strategy enables controlled engineering of large focal gene amplifications via ecDNAs.
- This approach provides insights into ecDNA's role in tumorigenesis.
- The method is valuable for studying ecDNA biology and developing preclinical cancer models.
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