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Competition for Space in Development and Diseases

Periodic Reporting for period 3 - CoSpaDD (Competition for Space in Development and Diseases)

Reporting period: 2021-01-01 to 2022-06-30

The tissues composing our body are incredibly dynamics. For instance, all the cells in the gut can be entirely renewed within 10 days. This suggests that cell proliferation has to be perfectly adjusted to the rate of cell elimination and cell death. While we know quite well the mechanisms that regulate cell proliferation or programmed cell death (also called apoptosis), how those two mechanisms are adjusted to tissue-wide information is not clear. While this adjustment is important in physiological conditions during embryogenesis and during tissue homeostasis, it may also be co-opted to kill preferentially one cell type. This mechanism of cell competition was characterised more than 40 years ago in the fruit fly Drosophila and is now becoming an intensive field of interest both in mammals and human cell culture. This context-dependent cell elimination can fine tune the composition of a tissue by eliminating suboptimal cells. However, it can also be exploited by tumoural cells to kill and replace their neighbours, hence accelerating tumour expansion.

In this project, we aim to characterise a specific mode of competition called "mechanical cell competition", where the mechanical stress can trigger preferential elimination of one cell population. We would like to better understand how cell deformation can trigger apoptosis in epithelial tissue and characterise signaling molecules that relay mechanical information in chemical signaling. We would like to understand how much the adjustment of cell death by mechanical input participate to the normal development of tissue, tissue size and tissue shape regulation as well as tissue homeostasis. Eventually, we would like to know how the same signals can be exploited by tumoural cells to induce neighbouring cell elimination and expand in the host tissue. The characterisation of compaction sensing and cell death induced by compaction will not only help to understand how cells coordinate in a tissue, but also may lead to the characterisation of cancer relevant targets that may help to slow down tumour expansion.
We managed to characterise a new function of the EGFR/ERK pathway in cell deformation sensing and cell death induction. Using the pupal notum (a single layer epithelium in the fly), we found that cell stretching can transiently activate ERK, which will downregulate caspase activation and cell elimination. Activation of growth in large clones through the expression of the oncogene Ras can compact the neighbouring cells, downregulate EGFR/ERK and trigger ectopic cell death. Accordingly, upregulation of ERK signaling in the neighbouring cells prevent cell elimination and slow down Ras clone expansion. This is one of the first characterisation of a pathway invovlved in mechanical cell competition in vivo (those results are published in an open access article in Current Biology, 2019).

We also started to dissect the mechanism of mechanosensing by screening for EGFR interactors and test their impact on deformation sensing in the notum. We are also trying to understand how much the modulation of cell death by ERK and mechanics contribute to tissue homeostasis and tissue development. Accordingly, we found that every dying cell activates transiently ERK in the direct neighbours through their stretching. This modulates the spatiotemporal distribution of cell elimination and helps to maintain tissue integrity. Importantly, this transient and local feedback has a very significant impact on the total number of cell death and provides a simple explanation for the capacity of the tissue to cope with local perturbations of the rate of cell death.

We are also trying to characterise the pattern of cell death in the wing imaginal disc and its contribution to clone dynamics and shape of the adult wing. We found that caspase inhibition significantly alter the adult wing shape as well as the imaginal disc shape. This is associated with a stereotypical pattern of cell death which influences the local probability of clone diseappearance. We are currently trying to connect the local clone dynamics and clonal competition with the robustness of adult shape.

Finally, we are characterising the conditions in which fast growing clones can deform and kill neighbouring cells. Using quantitative live imaging in the pupal notum, we found that different modes of compaction can coexist : compaction driven by growth or compaction driven by increased line tension at clone boundaries. To better predict in which conditions those two modes will lead to cell competition, we are performing 2D vertex modeling of those two modes of compaction and try to predict in which conditions they will lead to cell elimination and clone expansion.

Lastly, we are also trying to characterise how cells engage in apoptosis and how caspases ochestrate the removal of cells from the epihelial layers.
By the end of the project, we hope to better understand how mechanics can help to orchestrate cell elimination in physiological conditions but also during competition. We should have a better understanding of the mechanisms of mechanosensing (mostly through EGFR/ERK) and a better understanding of how tissue can cope with local perturbations and adjust locally cell elimination. This project will also characterise new mechanisms at play allowing the elimination of aberrant cells or promoting the expansion of tumoural cells. Altogether, we hope to better understand how tissue can self organise and how cells communicate within the tissue to adjust the local rate of cell death.
Ras clones (purple) deforming the neighbouring cells (green: E-cad marking the cell contour)