Cell Competition: How to Take Over the Space Left by Your Neighbours

HAL Id: hal-02644837

https://hal.archives-ouvertes.fr/hal-02644837

Submitted on 28 May 2020

HAL

is a multi-disciplinary open access archive for the deposit and dissemination of sci- entific research documents, whether they are pub- lished or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers.

L’archive ouverte pluridisciplinaire

destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d’enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

Cell Competition: How to Take Over the Space Left by Your Neighbours

Romain Levayer

To cite this version:

Romain Levayer. Cell Competition: How to Take Over the Space Left by Your Neighbours. Current

Biology - CB, Elsevier, 2018, 28 (13), pp.R741-R744. �10.1016/j.cub.2018.05.023�. �hal-02644837�

Cell competition: How to take over the space left by your neighbours?

Romain Levayer^1*

1. Institut Pasteur, Department of Developmental and Stem Cell Biology, 25 rue du Dr. Roux,

75015 Paris, France

*: Correspondence to: [email protected]

Summary

Fast growing cells can expand in a tissue by eliminating and replacing the neighbouring wild type cells through apoptosis. A new study provides an elegant explanation on how cell elimination contributes to the preferential expansion of the invading population.

Main text

Developing tissues have the amazing capacity to cope with perturbative conditions and yet produce harmonious tissues with the right size and proportion. This robustness is based on the capacity of every single cell to adjust its fate/behaviour to changes in the tissular environment.

This includes the modulation of cell death which for instance can contribute to the elimination of supernumerary cells, misspecified cells and/or viable but suboptimal cells. Cell competition is a process inducing a context dependent elimination of one cell population by another through apoptosis[1, 2]. This conserved mechanism was proposed to promote the expansion of fast growing pretumoral cells (so called super-competitors) through the elimination and replacement of the neighbouring wild type (WT) cells. Most of the studies focused so far on the characterization of the mechanism(s) triggering apoptosis in the outcompeted cells. This includes strictly contact dependent death induction based on the interactions of transmembrane proteins[3-5], cell elimination induced by diffusive factors[6], and/or elimination triggered by mechanical stress and cell compaction[7, 8]. While the exact location of cell death events can vary in all those scenario, most of the cell eliminations described so far occurs close to super-competitive clone boundaries (less than 5-6 cell rows away from the boundaries). Yet there was so far no study analyzing the influence of the location of eliminated cells on super-competitive clone expansion.

The major goal of super-competition studies is to understand how one cell population can replace another one and occupy a tissue. However there was surprisingly relatively much less focus on how cell elimination could contribute to clone expansion. Several studies already showed that apoptosis inhibition significantly reduces the expansion of super-competitor clones[9-11].

Moreover, cell elimination can induce several compensatory mechanisms that could contribute to

super-competitive cell expansion, including compensatory cell proliferation[12], stem cell expansion through symmetric divisions[13], and/or compensatory cell volume growth[14].

However the contribution of those mechanisms to the expansion of the clones was not tested experimentally and there was up to now no explanation on how they will be biased toward more expansion of the super-competitive clones.

In this issue, Tsuboi and colleagues address elegantly the question of how cell elimination contributes to clone expansion. By combining theoretical and experimental work, they propose that biased junction remodelings occurring during WT cell elimination promote pretumoral cell area expansion and accelerate tissue invasion[15]. Using mechanical modeling of a 2D epithelial layer in silico (vertex model) combined with in vivo experiments in Drosophila, they first confirmed that induction of hyperproliferative clones through Hippo pathway downregulation could stretch neighbouring cells along clone boundaries (Figure 1), as previously observed in wing imaginal disc[16, 17]. They then performed live imaging of competition by generating super-competitive clones expressing an active form of Yki (Drosophila Yap/taZ) or an active form of Ras (two well- known regulators of cell growth and survival) in the pupal notum (a single layer epithelium). To dissect the process of clone expansion, they first tracked systematically the evolution of the apical area of cells next to a WT extruding cell at the clone boundary (Figure 1). Interestingly, they observed that the apical area of super-competitive cells increased significantly more than WT cell area upon cell elimination, suggesting that the space left by the extruding cells was preferentially occupied by the clone. More importantly, this bias was higher when the WT dying cell was elongated along clone boundary and was mostly restricted in the cells directly contacting the extruding cells. Those experimental observations could be recapitulated in the vertex model by increasing the proliferation rate in clones and inducing WT cell death at clone boundaries for a wide ranges of mechanical conditions.

Why is then the area increasing more in super-competitive cells compared to WT cells? Tsuboi

and colleagues proposed and tested two hypothesis. The relative increase of the

proliferation/growth rate in clones generates compressive forces within the clone (due to limited

space in the tissue) [18]. As such, WT cell elimination would release mechanical constrain and

trigger preferential expansion of the compressed super-competitive cells. However, there was

little correlation between the degree of super-competitive cell compaction (using cell area as a

proxy) and their capacity to expand following neighbouring cell death. Moreover, releasing

compressive forces within the clone in the vertex model did not prevent the biased area increase

following cell elimination. This was suggesting that another mechanism was responsible for this

bias. Therefore, the authors started to study the evolution of cell topology and the junction remodeling events induced by cell extrusion. Interestingly, the increase of cell apical area in super-competitive cells correlated with an increase of the number of neighbours, in agreement with the so called Lewis law which describes a positive correlation between cell area and cell sidedness. This was suggesting that junction remodeling could contribute to area expansion. It was recently suggested that shorter junctions are more likely to be remodeled because of random length fluctuations[19]. Accordingly, Tsuboi and colleagues observed a higher rate of junction remodeling of the short edges of the stretched WT cells which are perpendicular to clone boundaries (Figure 1).

Could this biased junction remodeling be responsible then for the bias in apical area evolution?

By analyzing theoretically and experimentally every potential conformation of cell-cell contacts, the authors could show that remodeling of the WT junctions perpendicular to the clone boundary will uniquely increase the number of sides of the super-competitive cells. Accordingly, junction remodeling of WT cell bounds perpendicular to the clone boundary were associated with a significant increase of super-competitive cell areas both

Altogether, this suggested that WT cell stretching driven by clone overgrowth combined with the competitive cell elimination at clone boundaries will accelerate clone expansion through biased junction remodeling and biased area increase (Figure 1). Yet, it remained unclear whether this short time scale phenomenon could impact clone growth on long time scale. While the bias junction remodeling cannot be perturbed easily experimentally, the authors used the vertex model to modify the distribution of junction remodelings at clone boundaries and the distribution of cell death. Interestingly clone growth was significantly faster when cell death was occurring next to clone boundaries. More importantly, clone expansion was significantly reduced when junction remodelings were occurring randomly at clone boundaries (with no bias for short/perpendicular junctions). Those simulations confirmed that the biases in junction remodeling and area expansion significantly accelerate super-competitive clone expansion.

This elegant model has several interesting consequences. First, it suggests that cell elimination at clone boundaries will contribute much more to clone expansion compared to more distant cell death. As such the different mechanisms of competition (see above) will not impact equally clone expansion depending on the distribution of cell death. This strengthens the need for more quantitative description of the distribution of cell elimination during each competition scenario.

This study also provides the first evidence that cell shape/anisotropy at clone boundary can

influence the expansion of super-competitive clones. WT cell stretching will only occur if the

mechanical stress produced by clone overgrowth is not dissipated in the tissue through a high rate of junction remodeling and/or cell division. Indeed, other competition scenarios are associated with a higher rate of cell mixing between the two cell types and are not associated with WT cell deformations[5]. Yet, the authors suggest that the topology associated with the elimination of a WT cell surrounded by several super-competitive cells will also favor biased area expansion of super-competitive cells. As such, this biased area compensation could apply to a wide range of competition scenarios. Interestingly, area compensation could also be coupled to compensatory proliferation, as cell area expansion was previously associated with increased proliferation rate[20]. Further work will help to elucidate the interplay between those different compensatory mechanisms and evaluate their relative contribution to clone expansion.

In summary, this study provides one of the first detailed descriptions on how cell elimination contributes to clone expansion. The recent development of long term imaging of cell competition should provide in the near future more quantitative descriptions of cell shape evolution and the distribution of cell death during each competition scenario. This will hopefully better elucidate how one cell population can benefit from the death of its neighbours.

References

1. Levayer, R., and Moreno, E. (2013). Mechanisms of cell competition: themes and variations. J Cell Biol 200, 689-698.

2. Vincent, J.P., Fletcher, A.G., and Baena-Lopez, L.A. (2013). Mechanisms and mechanics of cell competition in epithelia. Nat Rev Mol Cell Biol 14, 581-591.

3. Rhiner, C., Lopez-Gay, J.M., Soldini, D., Casas-Tinto, S., Martin, F.A., Lombardia, L., and Moreno, E. (2010). Flower forms an extracellular code that reveals the fitness of a cell to its neighbors in Drosophila. Dev Cell 18, 985-998.

4. Yamamoto, M., Ohsawa, S., Kunimasa, K., and Igaki, T. (2017). The ligand Sas and its receptor PTP10D drive tumour-suppressive cell competition. Nature 542, 246-250.

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

6. Senoo-Matsuda, N., and Johnston, L.A. (2007). Soluble factors mediate competitive and cooperative interactions between cells expressing different levels of Drosophila Myc. Proc Natl Acad Sci U S A 104, 18543-18548.

7. Wagstaff, L., Goschorska, M., Kozyrska, K., Duclos, G., Kucinski, I., Chessel, A., Hampton-O'Neil, L., Bradshaw, C.R., Allen, G.E., Rawlins, E.L., et al. (2016). Mechanical cell competition kills cells via induction of lethal p53 levels. Nat Commun 7, 11373.

8. Levayer, R., Dupont, C., and Moreno, E. (2016). Tissue Crowding Induces Caspase-Dependent Competition for Space. Curr Biol 26, 670-677.

9. Moreno, E., and Basler, K. (2004). dMyc transforms cells into super-competitors. Cell 117, 117- 129.

10. Suijkerbuijk, S.J., Kolahgar, G., Kucinski, I., and Piddini, E. (2016). Cell Competition Drives the

Growth of Intestinal Adenomas in Drosophila. Curr Biol 26, 428-438.

11. Eichenlaub, T., Cohen, S.M., and Herranz, H. (2016). Cell Competition Drives the Formation of Metastatic Tumors in a Drosophila Model of Epithelial Tumor Formation. Curr Biol 26, 419-427.

12. Martin, F.A., Perez-Garijo, A., and Morata, G. (2009). Apoptosis in Drosophila: compensatory proliferation and undead cells. Int J Dev Biol 53, 1341-1347.

13. Kolahgar, G., Suijkerbuijk, S.J., Kucinski, I., Poirier, E.Z., Mansour, S., Simons, B.D., and Piddini, E.

(2015). Cell Competition Modifies Adult Stem Cell and Tissue Population Dynamics in a JAK-STAT- Dependent Manner. Dev Cell 34, 297-309.

14. Tamori, Y., and Deng, W.M. (2013). Tissue repair through cell competition and compensatory cellular hypertrophy in postmitotic epithelia. Dev Cell 25, 350-363.

15. Tsuboi, A., Ohsawa, S., Umetsu, D., Sando, Y., Kuranaga, E., Igaki, T., and Fujimoto, K. (2018).

Competition for space is controlled by apoptosis-induced change of local epithelial topology.

Current Biology.

16. Legoff, L., Rouault, H., and Lecuit, T. (2013). A global pattern of mechanical stress polarizes cell divisions and cell shape in the growing Drosophila wing disc. Development 140, 4051-4059.

17. Mao, Y., Tournier, A.L., Hoppe, A., Kester, L., Thompson, B.J., and Tapon, N. (2013). Differential proliferation rates generate patterns of mechanical tension that orient tissue growth. EMBO J 32, 2790-2803.

18. Shraiman, B.I. (2005). Mechanical feedback as a possible regulator of tissue growth. Proc Natl Acad Sci U S A 102, 3318-3323.

19. Curran, S., Strandkvist, C., Bathmann, J., de Gennes, M., Kabla, A., Salbreux, G., and Baum, B.

(2017). Myosin II Controls Junction Fluctuations to Guide Epithelial Tissue Ordering. Dev Cell 43, 480-492 e486.

20. Aragona, M., Panciera, T., Manfrin, A., Giulitti, S., Michielin, F., Elvassore, N., Dupont, S., and Piccolo, S. (2013). A mechanical checkpoint controls multicellular growth through YAP/TAZ regulation by actin-processing factors. Cell 154, 1047-1059.

Figure Legends

Figure 1: Biased junction remodelings trigger super-competitive clone expansion

Top: Super-competitive cell overgrowth (green) produces compressive forces within the clone

and stretch the neighbouring WT cells (purple). Progressive elimination of the WT cells (red) at

clone boundary contributes to fast clone expansion.

events occurring during the extrusion of one WT cell next to the clone boundary. Shorter junctions

perpendicular to the clone boundaries (orange) are preferentially remodeled, leading to a net gain

of sides and area for neighbouring super-competitive cells compared to WT cells. Green junctions

are newly formed junctions.

WT cells

Differential growth

Figure 1

Neighbouring cell distortion + boundary cell death

Boundary cell

extrusion/death Biased interacalation

(perpendicular to clone boundary)

+

= +

-

= - +

+

=

Net area/junction gain in super-competitive cells

Gain/loss of junctions super-competitive cells

dying/extruding cells

Accelerated

clone expansion