A milestone moment for team eDyNAmiC
A milestone moment for team eDyNAmiC and the ecDNA field.
eDyNAmiC
Led by Dr Paul Mischel (Stanford Medicine, USA).The challenge
eDyNAmiC is tackling the extrachromosomal DNA challenge, seeking to understand how these small circular DNA particles enable tumours to evolve and evade treatment. While extrachromosomal DNA (ecDNA) was first observed in cancer cells back in 1965, its importance was only starting to come to light at the time the challenge was set in 2020. The field was just starting to appreciate how widespread ecDNA may be. It was emerging as a driver of tumour evolution, allowing cells to rapidly change their genomes, potentially promoting aggressive tumour behaviour, drug resistance and poorer patient survival. But questions about ecDNA remained unanswered. How does it form and function? How does it evade the immune system? How does it enable tumour evolution? Can we find its vulnerabilities and target them to benefit patients? Team eDyNAmiC aims to foster bold collaborations and innovative solutions to interrogate all aspects of ecDNA biology and potentially launch a new field of cancer therapeutics.
At a glance
Funded in 2022
Institutions 13
Locations UK, US, Germany
Specialisms cancer biology, genetics, chemistry, evolutionary biology, computer science, maths and clinical research
eDyNAmiC is funded by
Team and leadership
eDyNAmiC is led by:
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 uniting seven areas of research, each aspirational yet grounded in substantial preliminary data and leveraging their unique expertise:
- 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 is opening up the ecDNA field, allowing rapid progress by establishing cutting edge experimental, computational and chemical biology tools, as well as deep datasets analysing tumours from thousands of patients, to allow the proper study of ecDNA. This includes adapting the CRISPR-CATCH technique, to profile ecDNA content and structure; presenting Amplicon Suite to characterise ecDNA from whole genome sequencing data; and developing single cell extrachromosomal circular DNA and transcriptome sequencing (scEC&T-seq). The team continues to develop cutting edge molecular and cell biologic techniques to study ecDNA structure and function, and has already established techniques to precisely generate and follow ecDNA in mouse and cell models.
Team eDyNAmiC is learning critical lessons by studying patients. In a landmark paper in Nature, the team showed that ecDNAs were present in oesophageal tissue before the development of cancer, highlighting the potential role of ecDNAs also at early stages, potentially driving transformation, with their presence predicting progression from Barrett’s oesophagus to oesophageal cancer. eDyNAmiC is also investigating the role of ecDNA in other tumour types, and collaborating with team PRECISION to explore the potential role of ecDNA in the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer.
In a subsequent spate of Nature papers, the team have published findings that significantly advance our understanding of ecDNA at all levels, from fundamental mechanisms through to their clinical impact, culminating in identifying the mechanism behind the first ecDNA-directed therapy, highlighting the power of this groundbreaking team.
By utilising the Genomics England Cohort, the team 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, allowing suppression of the immune system. 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 had shown that random inheritance of ecDNA results in extreme intratumoral heterogeneity and allows tumours to dynamically adapt and evolve, quickly selecting for clones which benefit them. The team went on to make the surprising discovery that inheritance of ecDNAs which cooperate to boost oncogene expression, can actually be coordinately inherited, going against Mendelian rules of inheritance. Thus allowing the maintenance of productive ecDNA interactions amidst random segregation.
The team has 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.
Looking ahead
eDyNAmiC has already made substantial progress towards its goals, but the team is far from done. Team eDyNAmiC is deepening our understanding of how ecDNA enables rapid tumour evolution and allows tumours to escape the immune system. By identifying and targeting the mechanisms involved, they are opening up the possibility of exploiting the presence of ecDNA therapeutically – improving outcomes for people with some of the hardest-to-treat types of cancer. Further, by expanding efforts in cutting edge chemical biology, eDyNAmiC is developing ways to identify and target ecDNA-proteins of interest that fall into previously undruggable classes, revolutionising treatment options.
To learn more, visit eDyNAmiC's website, which is managed and updated by the team itself.
We want to bring new hope to patients and have assembled an aspirational, ambitious programme, which could happen only under the auspices of Cancer Grand Challenges.
Paul Mischel (Team Lead, eDyNAmiC)
Stanford Medicine
