Tissue Crowding Induces Caspase-Dependent Competition for Space

Abstract

SummaryRegulation of tissue size requires fine tuning at the single-cell level of proliferation rate, cell volume, and cell death. Whereas the adjustment of proliferation and growth has been widely studied [1, 2, 3, 4, 5], the contribution of cell death and its adjustment to tissue-scale parameters have been so far much less explored. Recently, it was shown that epithelial cells could be eliminated by live-cell delamination in response to an increase of cell density [6]. 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 [6]. Studying the elimination of cells in the midline region of the Drosophila pupal notum, we found that, contrary to what was suggested before, Caspase 3 activation precedes and is required for cell delamination. Yet, using particle image velocimetry, genetics, and laser-induced perturbations, we confirmed [6] that local tissue crowding is necessary and sufficient to drive cell elimination and that cell elimination is independent of known fitness-dependent competition pathways [7, 8, 9]. Accordingly, activation of the oncogene Ras in clones was sufficient to compress the neighboring tissue and eliminate cells up to several cell diameters away from the clones. Mechanical stress has been previously proposed to contribute to cell competition [10, 11]. These results provide the first experimental evidences that crowding-induced death could be an alternative mode of super-competition, namely mechanical super-competition, independent of known fitness markers [7, 8, 9], that could promote tumor growth.

Slit-Robo Repulsive Signaling Extrudes Tumorigenic Cells from Epithelia

“…In the course of the above experiments, we observed that scrib cells were often not located in the main epithelium (disc proper, DP) but instead were extruding basally (orange asterisks, Figures 4A and 4B) or into the lumen (blue asterisks, Figures 4A and 4B). While cell extrusion is a central mechanism for enforcing cell competition in mammalian cell culture systems (Hogan et al, 2009), certain in vivo studies have suggested that extrusion passively follows cell death (Lolo et al, 2012; Levayer et al, 2016). We therefore tested the effect of caspase inhibition on scrib cell extrusion and found that extrusion still occurred: large masses of basally extruding scrib cells were displaced away from the DP (Figure 4C, quantified in Figure 4M).…”

Rab5-regulated endocytosis plays a crucial role in apical extrusion of transformed cells

“…The activation of myosin-II generates pulling-forces exerted at the interface between normal and transformed cells, thereby promoting apical extrusion of the transformed cells (6). Along the same line, recent studies have revealed that physical forces or mechanical tensions can play a crucial role in cell competition between normal and transformed epithelial cells (32,33). Thus, the EPLIN-myosin-II pathway could be another endocytosismediated regulatory mechanism for apical extrusion.…”

Survival of the Fittest: Essential Roles of Cell Competition in Development, Aging, and Cancer

“…This scenario would correspond to a situation where winner and loser cells have a different 'homeostatic pressure' [62,63], a pressure value at which growth and cell elimination are balanced in the tissue. Accordingly, recent results suggest that the contribution of caspases in crowding-induced delamination may have been overlooked in the Drosophila pupal notum [64]. As such, the activation of the oncogene Ras in clones, which promotes growth and prevents apoptosis [65,66], was sufficient to deform the neighboring tissue and induce ectopic cell death and cell delamination up to several cell diameters away from the clone, independently of the fitness machinery (flower, azot).…”

“…Alternatively, cell competition has been proposed to contribute to tissue size regulation [8]. Although cell death only has a minor contribution to final wing size [8,76], this may be relevant for other morphogenetic processes that trigger local tissue crowding and competition for space [60,61,64].…”