MechDeath · Study of the mechanical cues driving cell competition and its role in pretumoral cell expansion
Horizon 2020 — Marie Skłodowska-Curie Actions
- Duration
- 2019-06-01 → 2021-05-31
- EU contribution
- €185,076
- Participants
- 1
- Scheme
- MSCA-IF-EF-ST
Lines connect the coordinator with its partners.
Results in brief
Study of the mechanical cues driving cell competition and its role in pretumoral cell expansion
The healthy function of our tissues is achieved by the adjustment of single cell behavior to tissue scale parameters. This adjustment, through the local cell proliferation-disapearance equilibrium is necessary for organ morphogenesis and adult tissue size regulation. Most studies have been focusing on cell growth and cell division while survival rate and cell death (apoptosis) has drawn little attention. Cell competition is the process by which cells with small proliferating rate and survival properties are forced to die by the surrounding cells. For example, cell competition ables the elimination of suboptimal healthy cells to limit the appearance of errors in our organs during embryogenesis. However, genetic mutation, usually found in tumor, can create cells with high growth and survival rate, called «super competitor », which will force the elimination of surrounding healthy cells. Using the Drosophila pupal notum, Dr. Levayer – the experienced researcher’s supervisor – recently proved that local compaction of WT cells by fast-growing and apoptosis resistant RasV12 clones can induce cell death in vivo. The initial working hypothesis of this project is that clonal overgrowth forces crowding in the clone and at its periphery. This will activate caspase preferentially in the cells sensitive to apoptosis (the WT cells), hence promoting the expansion of the fast growing clones. In this project, the experienced researcher (ER) aim to characterise the mechanical conditions allowing cell elimination and define where and when mechanical competition contribute to cell competition and if it can significantly support pretumoral cell expansion. This project is divided in three objectives: Work Package 1 (WP1): Building a predictive framework linking single cell deformation, local mechanical cues and the probability to trigger apoptosis. WP2: Quantitatively characterise the contribution of mechanical cues to cell elimination in pretumoral competition scenarios. WP3: Exploring the parameters modulating mechanical cell competition and pretumoral clone expansion in silico and in vivo. First, in this project, the ER correlated mechanics with activity of the EGFR/ERK signaling pathways in physiological context as well as in pre-tumoral contexts. He especially observed that tissue stretching/compaction triggers an increase in cell survival/death probability. The ER proved that dying cell stretch their neighbours which activate in turn the EGFR/ERK prosurvival pathway and protect these cells for about one hour. This process is especially important to keep epithelial integrity safe. Third, the ER carefully analysed the behavior of mutant clones in multiple genetic condition associated to perturbation of cell growth, cell proliferation, cell death and cell forces. Along these quantifications, the ER managed to extract two independent mechanical conditions which are sufficient to generate the phenotype of mechanical cell competition: growth versus cell tension.
Data: CORDIS, © European Union
Project objective
The local equilibrium between cell proliferation and cell disappearance in epithelia is at the origin of the healthy function of our tissues and of their remarkable plasticity as observed in organ morphogenesis and adult tissue size regulation. Cell competition is the process by which cells with small proliferating rate and survival properties are forced to die through apoptosis by the surrounding cells. For example, cell competition enables the elimination of suboptimal healthy cells to limit the appearance of errors in our organs. However, activation of some oncogenes related to cell growth and cell survival in clones can drive the elimination of wild type (WT) neighboring cells and promote the expansion of the pretumoral population. Because many pathways altering cell growth and survival can trigger cell competition, there is no unique model of how cells induce death in their WT neighbors. Using the Drosophila pupal notum, it has been recently proved that local crowding and compaction of WT cells by fast-growing and apoptosis resistant clones can induce cell delamination in vivo, and that caspase activation is necessary for those cell extrusions. A similar “mechanical competition” was also described in mammalian MDCK cells. However, the exact mechanical cues driving cell elimination and the signaling pathway involved in this mechanotransductive process are still not known. Moreover, their contribution to pretumoral cell expansion has never been addressed in vivo. In this project, the experienced researcher will use Drosophila to i) characterise the mechanical conditions triggering cell elimination at the single cell level in vivo, ii) quantify the contribution of mechanical competition in cell competition scenarios implying oncogene proteins, and iii) define extensively where and when mechanical competition can promote pretumoral cell expansion through in silico predictions and in vivo validations.
Original text from CORDIS.
Participants
- INSTITUT PASTEUR · ParisCoordinatorFrance
Links
Data: CORDIS, © European Union