Modeling Extrachromosomal Oncogene Amplifications

Extrachromosomal circular DNAs (ecDNA) are megabase-sized DNA circles that can encode oncogenes, driving high copy-number amplification. ecDNAs are estimated to be present in approximately 17% of all tumors with higher prevalence in certain tumor types including glioblastoma & sarcomas. We have generated several mouse models where we can spatiotemporally induce ecDNA formation of Myc, Mdm2, and other oncogenes commonly found as ecDNA. We are presently focused on characterizing these models and believe they will aid in preclinical efforts towards targeting these aberrant structures. Currently, we are exploring several tumor types which harbor ecDNA, including liposarcoma, glioblastoma, small cell lung cancer, and pancreatic cancer.

Figure | a, Schematic of the Mdm2ec allele. b, Mdm2ec/+ MEFs approximately 5 weeks after being infected with AdCre or left untreated.
Figure | a, Schematic of the Mdm2ec allele. b, Mdm2ec/+ MEFs approximately 5 weeks after being infected with AdCre or left untreated. Repeated on three independent MEF lines. c, Metaphase spread and DNA FISH showing the presence of multiple Mdm2-positive ecDNAs in AdCre-infected Mdm2ec/+ MEFs (inset). Repeated twice.