During Year 1, we tightly integrated as a team. We developed new pioneering technologies, derived novel insights about ecDNA biology, and leveraged powerful clinical studies and infrastructure to learn from patients. We forged new collaborations with other Cancer Grand Challenge teams and with TRACERx, setting the stage for Year 2. We highlight 10 areas of Year 1 research impact below:
- Developed powerful new technologies to study ecDNA formation, including generating a mouse genetic model of ecDNA-driven cancer;
- Developed CRISPR-CATCH, a transformative technology for ecDNA isolation from tumour cells and clinical samples, revealing new insights into ecDNA transcription, including enhancer-only ecDNAs;
- Probed the landscape of cGAS/STING pathways in ecDNA+ cancers and demonstrated the feasibility of reinvigorating innate immunity as a potential approach to enhance anti-tumour immunity in ecDNA+ cancers;
- Deployed a powerful, searchable, chemo-proteomic platform to identify ligands that may modulate ecDNA proteins of interest;
- Characterized ecDNA in the Genomics England, TRACERx and PEACE Cohorts, comprising 14,757 patients, including primary and metastatic samples in 16 tumour types, including with correlative tissue studies. These studies are conducted in partnership with the TRACERx/ TRACERx Evo team;
- Incorporated analysis of mutational signatures into our understanding of ecDNA biology;
- Quantified ecDNA evolutionary dynamics and their impact on tumour evolution and treatment resistance;
- Demonstrated that ecDNA can occur in pre-cancer, arising during the transition from dysplasia in Barrett’s esophagus to esophageal adenocarcinoma, conducted in collaboration with the Fred Hutchinson Cancer Center and Rebecca Fitzgerald’s Cambridge cohort;
- Developed enhanced practical ecDNA diagnostics that deploy new image analysis methods and build on the evolutionary dynamic insights described in highlight #7;
Published highly visible and impactful papers in Nature and Nature Genetics (one with journal cover) – 6 research papers, 4 reviews, and 3 preprints – with more papers under review; had review articles published in Nature Reviews Genetics, Nature Reviews Clinical Oncology (journal cover), Nature Reviews Structural Biology, and others.
