Cells with high levels of p53 (green) become hypersensitive to crowding and succumb to p53 mutant cells by mechanical cell competition.
New finding that cells compete for space by squeezing each other to death suggests possible tactic by cancer cells
Wagstaff L et al. (2016) Mechanical cell competition kills cells via induction of lethal p53 levels. Nature Communications 7, Article number: 11373
Watch mechanical cell competition in action in this video from the paper
Fitter cells squeeze neighbouring cells to death, making room in which they can divide and expand rapidly, according to new research from Dr Eugenia Piddini’s lab at the Gurdon Institute, University of Cambridge.
The focus of the Piddini lab is cell competition, which has so far been understood to depend on exchange of biochemical signals to determine winners and losers in the fight for space and survival. This new study, which was led by postdoctoral researcher Laura Wagstaff and colleagues in the Piddini group, shows that cells can also compete by squeezing other cells, with winners surrounding and compacting losers, leading to their elimination.
Tissues in the body have an ‘ideal’ density for normal functioning, and the cells that make up each tissue can sense whether the density is healthy, too sparse (therefore requiring cell proliferation) or too crowded (requiring loss of cells by cell death). A process known as ‘mechanical cell competition’ occurs when cells that have different ideal densities are present in the same place and fight for space. Mutant cells that are more sensitive to high density become mechanical losers against normal cells.
What makes the results particularly exciting is that the mutants’ sensitivity to squeezing was associated with high levels of p53, a gene known to be activated by stress, such as lack of oxygen or glucose, or DNA damage. “This suggests that stressed and damaged cells may be eliminated from tissues by mechanical cell competition, and that this might help keep tissues healthy,” comments Dr Piddini.
Many cancers, on the other hand, lack the normal activity of p53. The team also observed that cells lacking p53 could kill cells with normal p53. On the basis of these results, Piddini speculates that because cancer cells have lost their p53 activity they lose their sensitivity to being squeezed; therefore they can squeeze their neighbouring host cells to death in order to continue to divide and grow in the crowded tumour environment.
The next step will be to move the experiments into the whole-animal model in mice to examine what happens in the three-dimensional tissue environment.
Article details and supporting material shared under a Creative Commons Attribution 4.0 International License.
More information on research in the Piddini group.