Evolution, sex and TRACERx: how cancer's 'spare tyre' helps it survive
Almost all animals have sex. That's to say, DNA from sperm and eggs is exchanged to create offspring with a mixture of both parents' genes.
It's the norm in plants too, where pollen from one plant fertilises another. Even bacteria have a primitive form of sex, where they extend an appendage, called the pilus, to pass DNA from one cell to another.
In evolutionary terms, this may seem counter-productive. Why would anyone want to pass on only half of their DNA to their offspring, instead of producing a clone asexually?
But for many species, this exchange of genetic material is essential to survival and has been consistently selected for throughout evolution.
And considering the alternative, it's easy to see why.
There are some organisms that have lost the ability to have sex—such as self-fertile roundworms, a fish called the Amazon molly and certain amoebae. Without the opportunity to reshuffle DNA between unrelated individuals, genetic errors build up.
This phenomenon is known as Muller's ratchet, and has been observed in many asexual organisms. Any bad mutation that's picked up by the organism—a turn of the ratchet—will be passed on to its offspring, with no way to revert to the original version of the gene.
When the offspring reproduces, these mutations are passed on again, along with any additional mutations acquired during its lifetime. With each generation, harmful mutations build up and the ratchet tightens, until the species is no longer viable.
Cancer cells are asexual
Cancer cells divide rapidly—picking up lots of DNA errors as they do so—and can be thought of much like an army of asexual amoebae. And our scientists working on TRACERx, our £14m project to understand lung cancer evolution, have used this comparison to explain a mysterious phenomenon observed in tumour cells.
Looking at a cancer cell under a microscope, you won't see the neatly packaged 46 chromosomes found in healthy tissue. Their DNA is in chaos, with sections of chromosomes exchanged, duplicated, or missing all together.
And in some cancer cells, scientists have noticed something even more unusual, known as whole genome doubling.
"When we look across tumours, and lung cancers in particular, we see that many of them have doubled their genome at some point in their evolutionary history. Almost every chromosome appears to have been duplicated, so there is far more DNA than in a normal cell," explains Dr. Nicky McGranahan, joint lead for the TRACERx team at University College London.
Until now, the reason for this had remained a mystery.
Cancer's spare tyre
"We thought there might actually be a survival advantage to cancer of doubling its genome. Cancer progression is an evolutionary process, and so the principals of Darwinian natural selection apply."
The team's theory was that having an extra copy of their genetic code, essentially a genetic spare tyre, could benefit cancer cells. If one copy of the genome gained a lethal mutation, the cell could continue to survive and divide, thanks to its second copy.
To test this, the researchers created a computer model to recreate the conditions of cancer evolution and determine whether, in theory, natural selection could favour whole genome doubling. And it turns out it did.
"Our simulations found that, given a sufficiently high rate of harmful mutations, evolution would favour genome doubling," explains McGranahan.
The results added weight to their theory, indicating that in the right circumstances, a second copy of the genome could benefit cancer cells by counteracting the negative effects of the DNA errors that build up as cancer cells divide.
But to really put the theory to the test, they needed more than models. For this, the team turned to lung cancer samples from people enrolled in the TRACERx study. And almost immediately ran into a problem.
Looking for bullet holes
"What's tricky about studying cancer evolution is that when we analyse a tumour, we're only looking at the cancer cells that are alive. This is in contrast to studying evolutionary biology, when we can look at the fossil record, which provides a wealth of information about the evolutionary dead-ends that didn't go anywhere."
According to McGranahan, it's similar to a problem faced by engineers and statisticians analysing planes coming back from the second world war.
"Many planes came back with lots of bullet holes in the fuselage, but instead of applying extra protection to these damaged areas, the statistician reasoned that the parts that were undamaged, such as the engine, needed to be reinforced. Planes that took a hit to the engine never made it back".
The team took a similar approach—looking at how many genetic bullet holes, or mutations, cancer cells could survive.
Publishing their work in Nature Genetics, the researchers found evidence of more genetic bullet holes after cancer cells had doubled their genome. This provided the evidence they were looking for that whole genome doubling does allow cells withstand more DNA errors and is favoured by natural selection.
The evolution of treatments
Using theories and methods developed by evolutionary biologists, this research has shed light on the complex development of cancer. But these findings don't only help us to understand the disease, they could also lead to new treatments.
The opportunity is two-fold, as McGranahan explains: "Whole genome doubling is a way for cancers to escape the harmful effects of Muller's ratchet. But this in itself is something we haven't really explored before, whether mutations in cancer cells could be harmful to the tumour. We hope to identify more of these weaknesses that could be exploited by new cancer drugs".
"And what's more, the fact that cancer cells so often double their genome is a key difference between cancer cells and healthy cells. A drug that specifically targets cells with doubled genomes, while leaving healthy cells unharmed, could lead to a new treatment for many different types of cancer".
Cancer has found a way to defy evolution and overcome the issues that afflict asexual amoebae as genetic errors build up. But with help from the TRACERx team, let's hope this could become its downfall.