The study, published in The Royal Society journal Open Biology and primarily funded by the Wellcome Trust, shows that two proteins called Rac and Rho are amongst the most important in a hugely complicated network of signalling molecules which drive cells to change into new shapes. The discovery means that in the future, targeting their levels in cancer cells could help prevent them from becoming metastatic.
In the study, researchers from The Institute of Cancer Research, London categorised more than 12,000 individual fruit fly cells into groups based on features of their shape, using a combination of genetics and computational analysis. They found that the cells fitted into only seven shape categories, one of which was only rarely seen in untreated cells.
Each of the seven types has distinctive features: for example differences in size, the presence or lack of protrusions caused by extensions to the cell cytoskeleton, roundness, or ‘ruffly’ edges.
The researchers devised a mathematical model to show that the transition from one cell shape to another could be explained by the effects of Rho and Rac.
The researchers believe the same two proteins governs shape changes in all animal cells, with other proteins that regulate the cytoskeleton fine-tuning cell shape and elaborating upon the basic shapes established by Rho and Rac.
Using a type of experiment called an RNAi screen, the researchers proved that changes to Ras and Rho levels can increase the diversity of cell shapes even within populations of genetically identical cells. This finding was important because it shows a way in which cancer cells can change their shape, and potentially become metastatic, without acquiring new genetic mutations.
In a series of computational experiments, the researchers also assessed the probability of each shape transforming into each of the others. Crucially, they found that cells tended to follow defined paths from one shape to another, rather than switching between types at random.
Dr Chris Bakal, Team Leader in the Division of Cancer Biology at the ICR, who led the study, said:
“Around 90 per cent of cancer patients die from metastatic disease, when cancer cells spread from a usually well-contained tumour to new areas of the body. The ability of cells to shape-shift is a crucial factor in metastasis, and we also know that the more cell shapes there are in a tumour, the worse the disease is predicted to be – so it’s important to better understand how and why cells change their shape.
“Our study goes some way to understanding the fundamental processes in eukaryotic cells that govern cell shape. It’s surprising and unexpected that the actions of only two proteins, amongst thousands, can cause very complex shape changes.
“An important finding was that rather than progressing from one state to another at random, cells change from one shape to another in an organised way in response to changes in the levels of just two proteins. The ability to change from one form to another is crucial in cancer metastasis because some shapes can migrate from one environment to another – such as through bone or soft tissue, or blood – but others cannot.
“This hints that in the future, we might be able to find treatments which take advantage of this staged process, reducing the chance that cancer cells will adopt the shapes that allow them to spread.”