‘Normal’ cells and ‘cancer’s surprising circular DNA’: Inside Cancer Grand Challenges Part 2

Last week, Cancer Grand Challenges, a global funding initiative co-founded by Cancer Research UK and the National Cancer Institute in the US, announced the funding of four new teams taking on the biggest challenges in cancer research today. 

After their announcement, we broke down two of the four challenges these new teams will be taking on, and heard from Professor Charles Swanton, our chief clinician and Cancer Grand Challenges Scientific Committee member, on what made them grand challenges. 

Now, we’re unpacking the other two, and introducing the global, multidisciplinary teams taking them on.  

Doing what previously wasn’t possible 

Cancers develop due to changes to our DNA, called mutations, that cause cells to multiply uncontrollably.  

The more mutations there are in a cell’s DNA, the more likely it is to become cancerous. But the presence of mutations doesn’t guarantee a cell will turn into cancer. In fact, recent research has shown that some cells are capable of functioning normally despite their DNA containing several mutations that would otherwise cause cancer.  

How these cells are able to remain ‘normal’ while other cells become cancerous is still a mystery, which raises a whole host of questions.  

What makes a cell ‘normal’? What triggers cells to become tumours? Why does that not affect all cells with mutations? And what effect does ageing, inflammation or exposure to carcinogens like chemicals in cigarettes have on those cells? 

Cancer Grand Challenges set the Normal Phenotypes challenge to find out. 

By uniting investigators with broad expertise in epidemiology, genomics, animal modelling, machine learning, community engagement and cancer prevention, the PROMINENT team, co-led by biologist and geneticist Allan Balmain, cancer epidemiologist Paul Brennan and computational biologist Núria López-Bigas, are bringing a new perspective to tackling fundamental questions on what causes cancer. 

What we want to do with this challenge wouldn’t even have been possible two or three years ago.

Paul Brennan, co-lead of the PROMINENT team.

But the PROMINENT team won’t be starting from scratch. Their work will build on the work of the previously funded Mutographs team investigating unusual mutation patterns, another challenge from Cancer Grand Challenges. 

Knowing why some cells become cancerous and others remain ‘normal’ will allow the team to look for new ways to prevent cancer developing in the first place. 

“Normal tissue can contain mutations. And what that tells you is that while mutations are necessary to induce cancer, they are not always sufficient, and there must be other stimulators of cancer,” says Swanton. 

“So, what’s promoting cancers in these tissues? What stimulates the birth of the first cancer cell that ultimately will go on to form the rest of the tumour?  

“This, I think is probably one of the greatest challenges in cancer medicine today, and one that I think we’re going to be able to unravel as a result of this Cancer Grand Challenge.” 

Bringing new hope to patients 

In our cells, DNA is tightly coiled into structures called chromosomes, which store all the genetic material we need for normal cell growth and survival. 

However, some small, circular pieces of DNA can exist in cells outside of chromosomes. This DNA is known as extrachromosomal DNA (ecDNA). 

Studies have shown that cancer cells have a lot of ecDNA in them, and these pieces of ecDNA often contain genes called oncogenes, which are the genes that have the potential to cause cancer.  

ecDNA can quickly change and multiply, and, thanks to recent research, it’s becoming increasingly clear that it plays a role in cancer’s ability to evolve and become resistant to treatment.  

But whilst we know that ecDNA plays a role in cancer biology, we don’t know how it evades the body’s immune system, or even how it forms. And that means we don’t know how to target it.  

To answer these questions, Cancer Grand Challenges invited teams to study ecDNA using the latest genetic technologies, and the eDyNAmiC team was deemed up to the Extrachromosomal DNA challenge. 

Inspired by strategies used by jazz musicians to think and work creatively, the team, led by Paul Mischel, is uniting mathematical modelling to predict tumour evolution and biology studies challenging the understanding of how a cell functions, as well as viewing what’s happening in patients in real time. 

By exploring new ways to target the unstable genomes of cancers, and drug currently undruggable targets, the eDyNAmiC team wants to give hope to people whose cancers are driven by ecDNA, and are usually some of the hardest to treat.  

“We’re just beginning to see how important ecDNA is in the evolution of tumours. It’s entirely unpredictable, entirely chaotic and very difficult to target,” says Swanton. 

“We need to understand ecDNA if we’re going to understand cancer drug resistance and this team will help us get to the heart of that problem much more quickly. We need to understand its biology, how it evolves, how its maintained, and ultimately how to target it.” 

A global effort 

The global community of investigators supported by Cancer Grand Challenges now stands at over 700 researchers, advocates, and partners from across 10 countries and 68 research institutions. 

By bringing together specialists that span multiple disciplines around the world that may not otherwise have the opportunity to collaborate, Cancer Grand Challenges is facilitating the truly innovative science we need to overcome the current barriers to progress in cancer research. 

“We have already seen during the pandemic what can happen when world-leading scientists transcend borders and focus on a common goal,” adds Michelle Mitchell, our chief executive officer.  

“As four more teams join the Cancer Grand Challenges global effort, we are gaining momentum in transforming patient outcomes and ultimately saving lives across the world.” 

Jacob