Squashed cancer turns tough

Scientists have made a remarkable observation about the behaviour of cancer cells. When they spread - or metastasise - inevitably they become much more robust, and less vulnerable to chemotherapy or the assault of the immune system. Many had speculated that this is just a product of the cancer equivalent of survival of the fittest, but, as he explains to Chris Smith, Gabriel Ichim, who’s at the University of Lyon, has found that fighting their way out of the tightly pressured environment of a tumour, and squeezing their way into the bloodstream, does something to the DNA of these cells, endowing them with their more resilient profile…

Gabriel - Cancer is very dangerous when it spreads through the body, and at this stage it is basically incurable. These cancer cells are resistant to cell death, but we don't know why the spread of cancer through the body is very stressful. From a point of view of mechanics, for the cells to spread, they really have to squeeze through tight places. Sometimes they are so stressed, they will explode. So putting these two points together, we wonder whether when they embark on this voyage, this stressful condition actually is responsible for this resistance to cell death.

Chris - You don't think it's just a survival of the fittest thing that some cells, which are a bit more robust and resilient and resistant to cell death are ones that are best equipped to handle the stress of breaking away from the parent tumour and going to a new part of the body.

Gabriel - That was actually the main question raised by the reviewers. And we did a series of experiments that is not a selection of a pre-existing population, as you said, that are resistant to death, but actually is something that is induced by this mechanical stress.

Chris - So this is effectively what doesn't kill you, makes you stronger. It really is true with these cancer cells that the physical pressures applied to them to get to a new part of the body changes their behaviour.

Gabriel - Exactly. There's another thing, it is not the strongest or the most intelligent who will survive, but those who can best manage a change. And so it's how you better adapt to the stress that will determine how fit you are to spread through the body.

Chris - So we'll come in a minute to actually what they're doing, but what is it that actually induces the change in the cells, or how do they detect that they're being stressed and how does that alter their behaviour to give them these additional abilities?

Gabriel - My opinion is that the nucleus is the limiting factor. Sometimes it explodes. So the DNA is getting released. Sometimes there are DNA damages and this mechanical stress therefore can be also metagenic. So when you stress the nucleus, this will be perpetuated to the next generation of cells. So, in my opinion, it starts with the stress on the nuclear level.

Chris - When we started talking, you pointed out that cells that do this metastasis appear to become much more resistant to, to dying. So therefore, whatever the process is that changes them. It changes them in that way. So how have you unpicked what is happening to the cells to make them more resistant? And how do you link that to this idea that it is the stress and perhaps doing things to the nucleus of the cell that makes them change their behaviour like that.

Gabriel - First of all, I'll have to tell you how we created these stressful conditions. We basically put lead weight on the cells. We created the compression that is found in tumours. We also use a membrane with very tiny pores; diameter is three micron. To give you an idea of the diameter of a nucleus, it's around 10 micron. And we found that only the constriction lead to increased survival of cancer cells. We wonder, okay, maybe how the genetic information that is translated change. And for this we've done RNA sequencing and these cells modified their message. They are telling us more about how they move, how they resist immuno-surveillance.

Chris - Given that you've now disclosed this, can we use this in a therapeutic way? Are there ways to exploit this phenomenon, perhaps the detectors or whatever the processes are that make the cells behave in this way? We can pre-empt that this is gonna happen and block the ability of the cells to respond in this way so that we have a new way to block metastasis, but also to target cancers.

Gabriel - Yes, our study was very descriptive. We simply describe these mechanisms. We left the door open for another researcher and maybe, they will take these findings further and find, as you said, better therapies to target these new mechanisms that we described. So we kind of opened a Pandora's box of ideas. Since mechanical stress is bronchogenic, we can consider a strategy to soften the tumours. There'll be no mechanical stress and like this, they will not have this survival too. There are ways to soften, to make tumours less hard, and then the last point, this mechanical stress cells become invisible to our own immune cells. So there may be ways to remove this invisibility cloth and enhance the killing by the immune cells. But this is something that, we didn't yet investigate. And then hopefully, there will be other researchers that will take the study further.