A caspase dependent competition for space

Cell growth, proliferation and death rates need to be adjusted to tissue scale parameters in order to maintain tissue size and shape. Using the Drosophila pupal notum (a single layer epithelium), we found that local crowding in the epithelium is sufficient to trigger caspase activation and cell delamination. The same mechanism drives the preferential elimination of cells neighboring fast growing clones resistant to apoptosis. This work suggests that competition for space may participate in tissue size regulation and may promote tumoral cell expansion through the elimination of the neighboring cells.

HFSP Long-Term Fellow Romain Levayer and colleagues
authored on Thu, 25 February 2016

Regulation of tissue size requires fine tuning at the single cell level of proliferation rate, cell volume and cell death. While the adjustment of proliferation and growth has been widely studied, the contribution of cell death and its adjustment to tissue scale parameters have so far been much less explored. Recently it was shown that epithelial cells could be eliminated by live-cell delamination in response to a local increase of cell density. Cell delamination was supposed to occur independently of caspase activation, and was suggested to be based on a gradual and spontaneous disappearance of junctions in the delaminating cells.  Studying the elimination of cells in the Drosophila pupal notum, we found that contrary to what was suggested before, caspase activation precedes and is required for every cell delamination event occurring in the notum. Accordingly, inhibiting apoptosis in the full tissue or in clones was sufficient to block delamination and we systematically observed caspase activity prior to cell delamination using different live reporters of caspase activity.

Figure: Model of tissue invasion through mechanical super competition
Schematic of the invasion of a wild type tissue by a clonal population with faster growth and resistant to apoptosis. Compaction of cells neighbouring the clone (middle) activates apoptosis and drives cell delamination, leading to space release and further growth of the clone.

Using Particle Image Velocimetry to track local tissue deformation, we confirm that local tissue crowding correlates with a high rate of cell elimination throughout the notum. Using laser wounding, we could perturb tissue flow locally and prevent cell delamination by blocking tissue crowding. Finally, conditional activation of the oncogene rasv12 in clones was sufficient to induce fast overgrowth and induce ectopic tissue crowding and cell elimination in the neighbouring tissue. We therefore confirmed that local tissue crowding is necessary and sufficient to drive cell elimination.

These results have several important consequences. First, they suggest that a yet unknown pathway can sense local tissue density and trigger caspase activation, independently of the most obvious candidates (JNK, Hippo signalling, p53), opening exiting perspectives in the field of mechano-transduction. Secondly, they suggest that cells can have differential sensitivity to mechanical stress. A relative increase of growth rate in clones will build up mechanical stress both within the clone and in the neighbouring tissue. If the modulation of growth is combined with resistance to apoptosis (like many oncogenes, such as Ras), our results predict that cell elimination will occur preferentially in the neighbouring tissue, hence allowing further space release and further clone expansion. We therefore propose that caspase dependent competition for space may contribute to early tumor expansion and tissue invasion.

Reference

Tissue Crowding Induces Caspase-Dependent Competition for Space. Levayer, R., Dupont, C. & Moreno, E. Current biology : CB, doi:10.1016/j.cub.2015.12.072 (2016).

Pubmed link

Current Biology link

Divide and rule: a new strategy of tissue invasion by pre-tumoral cells (also by Romain Levayer)