STRESS SIGNALLING IN TUMOUR CELLS

Last week I told you about a breakthrough discovery that lead to the development of a new drug that targets 22 different types of cancers.

This week I am eager to share about another exciting development our team has been focusing on: stress signalling in tumour cells. In particular, how tumour cells adapt to stress.

The idea is that when tumour cells grow in a certain environment, that environment then has the capability to ‘stress’ the tumour cells – for example, there might not be enough oxygen, there might be an immune cell attack or DNA damaging agents that then activate the stress pathways in the tumour cells.

We believe that the way tumour cells adapt to stress is part of how they become resistant to therapies and can become more aggressive.

So rather than focusing on genomic changes, we’ve become really interested in very rapid changes in cell wiring that can allow cells to survive these stresses in an acute way.

Let’s say you suddenly took the oxygen away from a cell. The cells that can somewhat hold their breath for a little bit until the oxygen comes back are the ones that are going to survive. And, maybe by rewiring in order to do that, that cell becomes more adapted to the next time that happens.

If these stresses are coming and going in the environment, then you can imagine ways that cells can become heartier; we hypothesize that this makes them more resistant to therapy.

We’re therefore really interested in what happens acutely within minutes of specific forms of stress: does that adapted process become locked in or does the cell have the ability to react that way right from the start?

It’s a new way of thinking about therapy. If you can figure out the pathway that a tumour cell activates to withstand stress, you can understand what the ‘players’ are and when you turn those off, then the cell doesn’t survive under stress.

By putting stress on the cells, we are trying to figure out what it is that they’re vulnerable to, and then we take away their ability to respond to that stress. Our main focus is for us to learn how to stress cells and then look at the rewiring (i.e. new biology) that gets activated under that condition, and how this leads to aggressive behaviour including enhanced metastatic capacity.
 

For example, if you take an organism and you cool down its environment and that organism fires up an internal furnace to withstand the drop in temperature, if you then clip the circuitry that allows it to turn on that furnace, it won’t survive.

We think that some of these changes that are required are so rapid, they need to change so quickly, that we have to focus on a different way for cells to change their biology. One of the ways we do that is something called mRNA (Messenger RNA) translation: the ability of an mRNA, a message, to get turned into a protein through activation of mRNA translation.

A protein can be made very quickly; transcription (going from DNA into RNA) might take hours to days. If there’s a sudden shift in temperature, the cell probably can’t wait hours to days to change – it will need to do something: crawl away, change its wiring, or turn on its furnace, within seconds. How does that happen? It’s become a really big part of what we’re focusing on, and we think that studying rapid changes in mRNA translation may hold the key to stress adaptation.

We’re still doing this predominantly in childhood solid tumours, where the genetics are, largely, much more simple than in adult neoplasms, so that you can more readily look at more direct drivers of disease. If there are single or only a few genetic drivers, then the genetic side of it is often the same across the different cell populations you’re looking at.

We believe understanding these stress pathways can teach us how to target vulnerabilities that can prevent cells from becoming therapy resistant and from gaining metastatic capacity.

Thanks for reading.

Poul