The Challenges: Professor Charlie Swanton discusses the extrachromosomal DNA challenge

17 February 2021
Charlie Swanton

In October, we posed 9 new challenges to the research community, each with the potential to change the way we think about cancer. Through our new blog series, members of our Cancer Grand Challenges Scientific Committee reflect on where a global, multidisciplinary team could take us with each challenge. Here, Professor Charlie Swanton shares his thoughts on extrachromosomal DNA. 

Genetic diversity drives evolution, providing a crucial mechanism for tumours to escape the pressures both of the immune system and of treatment. This is a major problem in the clinic. We can treat a person with chemotherapy, immunotherapy, targeted therapy – but their tumour can still evolve and become resistant to treatment.

Extrachromosomal DNA (ecDNA) is an extreme route to evolution, as cells rapidly alter their gene dosage to cope with an environmental insult. What interests me is the way ecDNA subverts what we originally understood to be the principles of evolution. These small, circular pieces of DNA develop and are inherited in a non-Mendelian, non-Darwinian manner, separate to normal chromosomal architecture. Importantly, the oncogenes they encode have massive transcriptional output. It's clear that ecDNA is playing by a different set of rules, and we are playing catch-up.

It’s worth highlighting that ecDNA isn’t unique to cancer cells – in fact, it’s commonly found elsewhere in nature, especially in single-celled organisms. The role it plays in these settings has clear parallels to what we observe in cancer. For example, recent findings demonstrated how ecDNA can help the weed Amaranthus palmeri become resistant to glyphosate weed killer. It’s interesting to consider what we could learn from other disciplines already studying ecDNA.

The whole phenomenon is fascinating. And yet, despite knowing since the 1970s that tumour cells might exploit these structures to become therapeutically resistant, and since the 1980s that ecDNA can harbour oncogenes, we still know very little about it. We’ve only recently appreciated how common ecDNA is in cancer – present in up to 40% of cancer cells – and the extent to which it drives tumour evolution, promoting aggressive tumour behaviour and poorer survival.

This is largely because the necessary tools to describe ecDNA in any great detail simply haven’t existed. But with the development and widespread use of techniques like whole genome sequencing and tools to piece together sequencing reads, we’re finally in a place to take a step back and answer a number of important basic questions. What are the mechanisms by which ecDNA is generated and how do these mechanisms subvert those that usually act to protect genomic integrity and stability? Which chromatin context favours the formation of ecDNA and high transcriptional output? To what extent does ecDNA generation simply represent the subversion of normal cellular processes that might be required to generate diversity under extreme environmental stress? And do we know for sure that ecDNA isn’t generated by normal human cells under stress, such as in the liver, to manage transient toxic stresses? 

Answering questions such as these could drive real progress in the clinic. We know, for example, that ecDNA can re-integrate with chromosomes to form homogenously staining regions (HSRs), acting like a bioreactor for further ecDNA generation. Could a deeper understanding of HSRs and their evolution pinpoint an opportunity to intervene? Knowledge gained through this challenge could even identify therapeutic approaches against historically undruggable targets that reside on ecDNA, such as MYC. To me, the opportunities for discovery are endless!

There is a real dearth of information surrounding ecDNA. But with this challenge we could unlock a whole new field of therapeutics. This Cancer Grand Challenge is the perfect opportunity to foster a collaborative, multidisciplinary approach and really interrogate this fundamental aspect of cancer biology.

Learn more about the extrachromosomal DNA challenge. For details on how to apply, click here.

With thanks to Dr Chris Bailey.