Divide and rule: a new strategy of tissue invasion by pre-tumoral cells [with video]

Cell competition is the mechanism that drives the elimination of slow proliferating cells (so called losers) by faster proliferating cells (winners) through apoptosis and can promote tumor expansion. By studying quantitatively cell competition through long term live imaging in Drosophila, we found that the probability of loser cell elimination correlates with the proportion of contact with winners and that winner cells actively mix with losers. The mixing increases the surface of contact between the two populations and accelerates loser elimination. This new mechanism could promote the invasion and the destruction of healthy tissue by pre-tumoral cells.

HFSP Long-Term Fellow Romain Levayer and colleagues
authored on Mon, 07 September 2015

Cell competition is a conserved mechanism required for correction of developmental errors and the maintenance of tissue fitness. The same mechanism can also be hijacked by pre-tumoral cells to induce apoptosis in neighboring cells and expand in the tissue. Elimination of the unfit cells (losers) is based on local communication with fitter cells (winners) through the membrane protein Flower. Apoptotic cells are preferentially found at the boundaries of patches of loser cells, which suggested that death induction is based on a shot range communication. Yet, this correlation remained qualitative and the exact location of the cells prior to death was still unknown. Confrontation of cells with different levels of the oncogene Myc was already known to induce competition. We performed for the first time long term live imaging of Myc-induced competition in the Drosophila pupal notum (a single layer epithelium, see Figure A and link to the movie). By systematically tracking the elimination of loser cells, we found that the probability of loser cell death correlated with the proportion of apical perimeter of contact shared with winner cells. Therefore, the form of the interface between loser and winner cells should modify the outcome of cell competition. Accordingly, modifying the shape of patches of loser cells by affecting cell-cell adhesion or tension was sufficient to affect the efficiency of loser cell elimination. Similarly, we could show that the natural poor mixing of cells from different lineages was sufficient to prevent cell competition through the reduction of surface of contact.

(click on image to enlarge)

Figure A: Snapshots of a movie showing epithelial cells in the Drosophila pupal notum marked with E-cad::GFP. The purple cells are a clone of loser cells (WT cells surrounded by cells overexpressing Myc).  The white arrowheads show delamination events. Scale bar= 10µm.
B: Model of the winner-loser mixing process and the subsequent acceleration of loser elimination and winner invasion. red arrows= increased interfacial tension, red lines = F-actin.

More surprisingly, we observed that the surface of contact between loser and winner cells was abnormally increased during competition. This was essential for efficient elimination of loser cells. Winner and loser mixing was driven by cell-cell intercalation, a mechanism allowing cells to swap their positions in the epithelial layer. Using genetic perturbations, we found that a relative increase of the membrane lipid phosphatidylinositol (3,4,5)-trisphosphate (PIP3) in winners was responsible for the high degree of mixing through two key parameters: firstly, through the relative growth decrease in losers and secondly, through the modification of F-actin distribution in junctions. Using laser nano-surgery, we showed that the relative increase of F-actin in winner-winner interfaces increased line tension in winner-winner contacts compared to winner-loser and loser-loser contacts. This led to a preferential stabilization of winner-loser interfaces and increased loser and winner mixing over time (Figure B).

So far, cell-cell intercalation was studied during embryogenesis. Our results suggest that cell-cell intercalation could also be involved in the early phases of tumor formation by promoting the invasion of the healthy tissue by pre-tumoral cells and accelerating the elimination and the replacement of the healthy cells.

Reference

Cell mixing induced by myc is required for competitive tissue invasion and destruction. Levayer, R., Hauert, B. & Moreno, E. Nature 524, 476-480, doi:10.1038/nature14684 (2015).

Link to article

Pubmed link