Scientists have found that ecDNA can encourage the growth of glioblastomas
An international team of scientists have shared how rogue rings of DNA that float outside of our chromosomes, known as extrachromosomal DNA, or ecDNA, can encourage the growth of a large proportion of glioblastomas, the most common and aggressive brain cancer in adults.
This discovery could lead to much-needed new approaches to diagnose glioblastoma early, track its progress and treat it more effectively.
The findings, published in Cancer Discovery, are the first to suggest ecDNA rings containing cancer-driving genes can appear in the earliest stages of glioblastoma's development, and in some cases, even before the tumour has fully formed. This early arrival could set the stage for the cancer's rapid growth, adaptability and resistance to treatment.
The study was led by Dr Benjamin Werner at Queen Mary University of London and Professor Paul Mischel at Stanford University, who are both part of Cancer Grand Challenges' team eDyNAmiC, as well as Professor Charlie Swanton at The Francis Crick Institute.
Cancer's toughest challenges
Glioblastoma is one of the most complex cancers to treat, with its median survival remaining at around 14 months and with little improvement made in recent decades. ecDNA is becoming a potentially important player in several adult and paediatric cancers, including glioblastoma, but its role remains mysterious.
The Cancer Grand Challenges initiative, founded by Cancer Research UK and the National Cancer Institute in the US, highlighted understanding ecDNA as one of the toughest challenges facing the field today.
In 2022, they funded team eDyNAmiC, a $25m international, cross-disciplinary consortium of experts in cancer, evolutionary biology, clinical research, computer science and mathematics, to decipher ecDNA's role and identify ways to target it. The current study is a significant advancement in team eDyNAmiC's work.
Uncovering a tumour's past
In the latest study, team eDyNAmiC and their collaborators integrated genomic and imaging data from patients with glioblastoma with advanced computational modelling of the evolution of ecDNAs in space and time.
Senior author Dr Benjamin Werner, a group leader at the Barts Cancer Institute, Queen Mary University of London, said, “We studied the tumours much like an archaeologist would. Rather than taking a single sample, we excavated multiple sites around the tumour, allowing us to build computational models describing how they evolved. We simulated millions of different scenarios to reconstruct how the earliest ecDNAs emerged, spread, and drove tumour aggressiveness, giving us a clearer picture of the tumour’s origins and progression.”
The analysis found that most ecDNA rings contained EGFR, a strong cancer-driving gene. EGFR ecDNA emerged early in the cancer's evolution, even before tumour formation in some patients. It also often gained extra changes, such as the EGFRvIII variant, which resulted in the cancer becoming more aggressive and resistant to therapies.
A new opportunity
Dr Magnus Haughey, a postdoctoral researcher in Dr Werner’s group and one of the paper’s lead authors, said, “These subtle mechanisms show that there may be a window of opportunity to detect and treat the disease between the first appearance of EGFR ecDNA and the emergence of these more aggressive variants.”
“If scientists can develop a reliable test to detect early EGFR ecDNA – for example, through a blood test – it could enable them to intervene before the disease becomes harder to treat.”
The study also established that ecDNA is capable of carrying more than one cancer gene at a time, each of which can shape how tumours evolve and respond to treatment, underlining the potential value of designing treatments based on a tumour's ecDNA profile.
Researchers are next planning to study how different treatments can affect the number and types of ecDNA in glioblastoma. Team eDyNAmiC will continue investigating the role of ecDNAs across multiple cancer types to find further opportunities to diagnose cancers at earlier stages, track their progression more accurately, and design more intelligent treatments.
Charlie Swanton, deputy clinical director and head of the Cancer Evolution and Genome Instability Laboratory at The Francis Crick Institute and chief clinician at Cancer Research UK, said: “These findings suggest that ecDNA is not just a passenger in glioblastoma, but an early and powerful driver of the disease. By tracing when and how ecDNA arises, we open up the possibility of detecting glioblastoma much earlier and intervening before it becomes so aggressive and resistant to therapy. I hope this might help to drive a new era in how we diagnose, track and treat this devastating cancer.”
Paul Mischel, MD, the Fortinet Founders professor and vice chair of research in the pathology department at Stanford Medicine, said: “These findings reveal an important new insight into the role of ecDNA in tumour development and progression. Previous work from our collaborative team and other researchers has shown that ecDNA can arise early in tumour development, including at the stage of high-grade dysplasia, and it can also arise later to drive tumour progression and treatment resistance."
"The findings here show that in glioblastoma, there is an early event driven by ecDNA that could potentially be more actionable, raising the possibility that glioblastoma is another cancer for which earlier detection and intervention based upon ecDNA may be possible.”
Director of cancer grand challenges, Dr David Scott, said: “This study exemplifies the bold, boundary-pushing science Cancer Grand Challenges was created to support. By unravelling the evolutionary history of ecDNA in glioblastoma, team eDyNAmiC is not only deepening our understanding of one of the most devastating cancers but also illuminating new paths for earlier detection and treatment. It’s a powerful reminder that when we bring together diverse disciplines and global talent, we can begin to solve the toughest problems facing cancer research.”
