It is remarkable that cancer cells can maintain and transcribe ecDNA, which is non-chromosomal, circular and does not have centromeres. We hypothesize that specific processes are necessary for ecDNA maintenance and transcription, and that disrupting them can cause loss of ecDNA-based transcripts and lead to cell death of ecDNA-positive tumor cells specifically.

Together with the lab of Richard Koche, we have shown that there are two subclasses of MYCN-positive ecDNA in neuroblastoma, one with proximal enhancers and one that hijacks distal enhancers (Helmsauer et al., Nature Comm., 2020). We also found that ecDNA passenger genes, such as DDX1, often found co-amplified with MYCN due to its genomic proximity, can lead to unexpected vulnerabilities. Targeting them causes strong tumor cell death in vitro and in vivo (Bei et al., Cancer Discovery, 2024).

One of the very recent lines of research in the lab is about cells losing ecDNA. Building on seminal work from Geoffrey Wahl and collaborators, we showed that under replicative stress, ecDNA moves into the cytosol, encapsulated in a micronucleus. We determined that cells that undergo ecDNA-micronucleation are more likely to die, and patients whose tumors show high micronucleation rates have better prognosis (Brückner et al., bioRxiv, 2025). We are currently investigating which processes ecDNA molecules require to be correctly segregated during cell division.