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Engineered extrachromosomal circular DNAs promote tumorigenesis (WGS)

ABSTRACT: Focal gene amplifications are among the most common cancer-associated mutations, but their evolution and contribution to tumorigenesis have proven challenging to recapitulate in primary cells and model organisms. Here we describe a general strategy to engineer large (>1 Mbp) focal amplifications mediated by extrachromosomal circular DNAs (ecDNAs) in a spatiotemporally controlled manner in cells and in genetically engineered 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 harboring 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 tumor formation in an autochthonous mouse model of hepatocellular carcinoma.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE264005 | GEO | 2024/10/05

REPOSITORIES: GEO

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Engineered extrachromosomal oncogene amplifications promote tumorigenesis (RNA-Seq)

Project description:Focal gene amplifications are among the most common cancer-associated mutations, but their evolution and contribution to tumorigenesis have proven challenging to recapitulate in primary cells and model organisms. Here we describe a general strategy to engineer large (>1 Mbp) focal amplifications mediated by extrachromosomal circular DNAs (ecDNAs) in a spatiotemporally controlled manner in cells and in genetically engineered 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 harboring 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 tumor formation in an autochthonous mouse model of hepatocellular carcinoma.

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Project description:It has been verified that extrachromosomal circular DNA (ecDNA) has important clinical significance, and the formation process of ecDNA, its immunogenicity, and its other functions have also been described. However, the balancing mechanism by which cells respond to ecDNA, i.e., how ecDNA degrades within cells, is unclear. Here, by using Circle-Seq method conducted on PLC-PRF-5 HCC Cells, ecDNA was purified and the samples were used for DNA Library Preparation and Next Generation Paired-End Sequencing using Illumina MiSeq Technology, We found that some ecDNAs disappeared after VD treatment compared with the DMSO group, and these disappearing ecDNA were related to EMT, proliferation, cell cycle, focal adhesion and other malignant behaviors. Moreover, Circle-seq peaks narrowed after VD treatment, and the coverage over the whole gene was significantly reduced, suggesting that ecDNA after VD treatment carried smaller DNA fragments, which may cause them not to function as a whole gene. Importantly, we demonstrate that VD can cause a continuous and steady decrease in ecDNA in HCC cells.

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