ecDNA functions as an evolutionary hotspot, allowing cancers to escape therapy after an initially promising response. We have shown that ecDNA in neuroblastoma is a major source of somatic rearrangements, leading to further circularization or to the reintegration of circular DNA into the linear genome (Koche et al., Nat. Genetics, 2020). In collaboration with the lab of Jan Dörr, we found that ecDNA-positive cells respond to chemotherapy by reducing the number of ecDNA molecules per cell and entering a senescent state. Combining chemotherapy with senolytic drugs (drugs that specifically target senescent cells) eradicates ecDNA-positive cells much more efficiently (Montuori et al., Cancer Discovery, 2025).

We hypothesize that continuous DNA repair processes generate a wide spectrum of recombination outcomes, and that those conferring the greatest cellular fitness are subsequently selected. To understand which spectrum of outcomes is possible, we are characterizing the processes involved in ecDNA repair and their footprints. A separate project investigates functional consequences of a particular recombination outcome, the reintegration of ecDNA into the linear chromosomes. Finally, we profile the structural and population-wide signatures that ecDNA evolution leaves in tumors.