Dog tumours sheds fresh light on cancer evolution

Scientists have long believed that cancer is a clonal disease, which means that each cell is a descendant of one original rogue ancestor. But what if cancer cells could grab other DNA sequences from their surroundings, including other cancer or even healthy cells, and augment their own genomes accordingly? For instance, to patch up a failing metabolic pathway to make the cells fitter, or acquire a gene coding for resistance to a chemotherapy drug. This is called “horizontal gene transfer”, and it’s been hypothesised for years. But now a new study has shown for the first time that it can really happen. Cambridge University’s Elizabeth Murchison had the ingenious idea of looking at transmissible cancers - where the cancer cells physically spread from one animal to another -  to see if she could spot this happening. In this case she was looking at an infectious canine cancer the genome of which has been roughly the same for about 8000 years. But, if the cancer picked up any genes from another dog it infected along the way, they would stand out because the genetic code would obviously be from a different animal. And that’s what she’s found. It's a discovery that challenges a core principle of cancer biology and opens the door to new ways of thinking about how cancers evolve in our own bodies, and how we might be able to treat them. We met up at Queens' College...

Elizabeth - We were interested in a very long-standing question in cancer biology, which is 'can cancer cells sometimes take up DNA from other cells of the body'? So normally when we think of cancer we think that there's one cell which has gone wrong in the body and that grows and divides abnormally and becomes a cancer. So the question we wanted to ask here was can cancer cells sometimes take up DNA from other cells of the body through a process known as horizontal gene transfer?

Chris - What would be the impact of doing that? Why does that matter, getting underneath that question?

Elizabeth - Well cancer evolves and that's how it acquires new traits, becomes more malignant and resists therapy and to evolve cancer cells need genetic variation and so this would be another mechanism for cancer cells to acquire genetic variation which may be fuel for natural selection and adaptive.

Chris - So if a cancer cell by chance became resistant to a drug I was using, if it could do what you're saying and pass genetic information to other cancer cells in the same tumour then it could potentially spread the ability to fend off that drug?

Elizabeth - Exactly yes, so it could be a mechanism for cancer cells to gain variation which was advantageous for cancer cell evolution.

Chris - I would anticipate though this is quite a hard nut to crack because when I get cancer, heaven forbid I haven't at the moment, but if a person has cancer it's their own cells with their own DNA. So how could you tell that that group of cancer cells has picked up another bit of your own DNA from somewhere else? It's not just a needle in a haystack, it's a haystack in a haystack.

Elizabeth - Exactly, that's why this is a long-standing question. I think the question was first proposed or the hypothesis that this occurs was first proposed more than 100 years ago and there have been many experimental studies which have suggested that cancer cells can indeed pick up DNA from other cells going in the lab and so on. But it's been really challenging to show that this really does occur in naturally occurring tumours for that very reason because the DNA of the patient and of the cancer are genetically so similar to one another. So it's been a real challenge.

Chris - And how have you got underneath it?

Elizabeth - So that's why we decided to look at this in a particular system that we work on which is transmissible cancers. So transmissible cancers are really rare diseases that occur in animals which occur when cancer cells themselves spread between individuals as infectious agents. So we know of cancers which have infectious involvement of a virus for instance like HPV, this is not like that. In these cases, transmissible cancers, the cancer cells themselves physically pass from one animal to the next and the one we particularly worked on in this study was in dogs. It's really fascinating because it actually first arose in one single dog that lived about 8,000 years ago. That cancer is actually still alive today by cancer cells passing from one dog to the next by mating. So it causes genital tumours and has spread to dogs all around the world. It's very common worldwide.

Chris - How does a dog tumour spread by mating answer the question, can cancer cells pick up other bits of DNA though?

Elizabeth - Yes, well because of the fact that in transmissible cancers the DNA of the host, the patient and the cancer are genetically completely distinct because the cancer actually came from another individual, a different dog. And so that means we can use genetics to distinguish what's host and what's cancer and using this we could look at whether DNA has been picked up by the cancer from host cells at some point.

Chris - So you've got this transmissible tumour and it's got the genetic code of the original dog from 8,000 years ago running it. It's like an organ transplant that's going from dog to dog to dog and your hypothesis is that if another dog along the way has added some DNA to that, it should stand out like a sore thumb because it will be genetically distinct.

Elizabeth - Exactly, that's the idea. We wanted to screen for DNA in this cancer which had come from another dog along the way in the transmission chain.

Chris - And did you find any?

Elizabeth - Yes, we did. We found an instance in tumours in dogs in India and Nepal and we were actually able to date when this had occurred by counting the number of mutations and it indicated that the horizontal transfer had occurred about 2,000 years ago. And so if you can imagine about 2,000 years ago this transmissible cancer infected a particular dog and we happen to know that this dog was probably somewhere in the Middle East and that dog actually passed some DNA from one of its own cells into this cancer and it's persisted there ever since.

Chris - So basically in the Middle East Jesus' dog had sex with another dog 2,000 years ago and added some of its own DNA to this canine tumour that was going round and you can still see that today proving that cancers do appear to be able to acquire genetic elements from whatever host they're in and in that way this opens up a new avenue really for understanding cancer biology.

Elizabeth - Exactly, yes. So it indicates quite clearly and for the first time in a naturally occurring tumour that cancer cells can sometimes take up DNA from their host cells and incorporate that DNA and we actually even found that the DNA that was taken up is expressing genes which means that it's providing new genetic potential, a new genetic repertoire to the cancer cell that it's become incorporated into.

Chris - We've dwelt very heavily on cancer but if it happens in cancer does this not mean it could be happening in healthy cells as well and this might be another really important thing whereby cells support each other or share information or actually how diseases evolve in the body too, not just cancer.

Elizabeth - Yeah and it's already very well known that mRNA, so RNA transcripts, can transfer between cells and this can have important roles to play in cell biology. Whether or not DNA itself can pass between cells and integrate and contribute to cell variation is not really well understood and this may well be, as you said, a common mechanism which is going on in our cells.