eDyNAmiC

Many of the eDyNAmiC members are pioneers in the ecDNA field. Led by Paul Mischel at Stanford Medicine, this international multidisciplinary team of scientists are exploiting cutting-edge, diverse approaches from cancer genomics, yeast genetics, epigenomics, artificial genome synthesis, longitudinal patient tracking, mathematical modelling, chemical biology, and immunology.

Tackling the extrachromosomal DNA challenge

The team has three overarching aims: 

• Identify the mechanisms of ecDNA generation, function and maintenance  

• Decipher ecDNA’s roles in tumour evolution driving cancer heterogeneity, progression and drug resistance  

• Identify targetable vulnerabilities of ecDNA-driven cancers

Team eDyNAmiC has continued to open up the ecDNA field by developing and sharing the experimental and computational tools needed to make ecDNA both measurable and experimentally tractable. Through a suite of technologies, including Amplicon Suite, the team has enabled researchers to identify and reconstruct complex ecDNA structures, characterise their function at single-cell resolution, and directly test their role in cancer initiation, evolution and therapeutic response. In a spate of papers, the team published findings that significantly advanced our understanding of ecDNA at all levels, from fundamental mechanisms through to their clinical impact and potential therapeutic approaches.

By utilizing the Genomics England Cohort, the team and its collaborators showed that of the 14,788 patients across 39 different tumour types, 17.1% contained ecDNA. Importantly, the presence of ecDNA was associated with tumour stage, metastases and decreased survival. The team went on to show that ecDNA doesn’t just amplify oncogenes, but also immunomodulatory genes. They also identified ecDNAs carrying just regulatory elements, such as promoters, enhancers and lncRNAs, highlighting the potential for cross regulation between ecDNA particles. The work also informed on the mutational processes associated with ecDNA formation and its subsequent progression.

eDyNAmiC has demonstrated that the random segregation of ecDNA during cell division generates profound intratumoral heterogeneity, enabling tumours to rapidly adapt and evolve. The team then made the unexpected discovery that ecDNAs which cooperate to enhance oncogene expression can be coordinately inherited, defying classical Mendelian principles and allowing productive ecDNA interactions to be maintained. The team went on to identify retention elements that facilitate inheritance of ecDNA in cancer cells. Together, these discoveries have transformed our understanding of ecDNA inheritance and maintenance, revealing fundamental mechanisms that sustain tumour evolution while uncovering promising new opportunities for therapeutic intervention.

By studying patient samples and developing novel model systems, the team has identified that ecDNA may play a role early in cancer development. The team demonstrated that ecDNA can be detected in Barrett’s oesophagus, where its presence is associated with progression to oesophageal cancer, and has also shown that ecDNA may contribute to the emergence of glioblastoma, suggesting that ecDNA can play a role in early cancer evolution. To investigate the consequences of ecDNA formation, the team developed the first genetically engineered mouse models of ecDNA-driven oncogene amplification. These studies demonstrate that ecDNA-mediated amplification is sufficient to drive cellular transformation and initiate tumorigenesis.

The team has also critically identified a therapeutic vulnerability of ecDNA containing cancers, showing that increased levels of ecDNA transcription leads to increased transcription replication conflict, which can be targeted by inhibiting CHK1. The team is exploring further vulnerabilities of ecDNA-containing cells and attempting to target them with first-in-class chemical probes.