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What regulates the spatiotemporal distribution of cell elimination in tissues remains largely unknown. This is particularly relevant for epithelia with high rates of cell elimination where simultaneous death of neighboring cells could impair epithelial sealing. Here, using the Drosophila pupal notum (a single-layer epithelium) and a new optogenetic tool to trigger caspase activation and cell extrusion, we first showed that death of clusters of at least three cells impaired epithelial sealing; yet, such clusters were almost never observed in vivo. Accordingly, statistical analysis and simulations of cell death distribution highlighted a transient and local protective phase occurring near every cell death. This protection is driven by a transient activation of ERK in cells neighboring extruding cells, which inhibits caspase activation and prevents elimination of cells in clusters. This suggests that the robustness of epithelia with high rates of cell elimination is an emerging property of local ERK feedback., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

The epithelium is one of the most abundant tissues in metazoans. It is required to generate stable chemical and mechanical barriers between physiological compartments (fluid matrix/external environment). This function is based on multiple intercellular junctions, which insulate and stabilize cell-cell contacts in the tissue. Despite this apparent robustness, epithelia can be extensively remodeled during wound healing, embryogenesis and tumor progression. The capacity to be remodeled while keeping tissue cohesion requires a perfect balance between stability and plasticity of intercellular junctions. The balance is partially regulated by intercellular adhesion, which is mostly based on adherens junctions and the transmembrane protein E-cadherin. The aim of this review is to report the molecular basis of the balance between plasticity and robustness in the epithelium. We will first present the minimal physical framework used to describe epithelial cell shape. We will then describe the main processes involved in intercellular adhesion regulation and their functions during epithelial morphogenesis. Eventually, we will analyze the relationship and the coupling between adhesive forces and cortical tension., (© Société de Biologie, 2012.)

Epithelial-mesenchymal transition, in which epithelial cells lose their polarity and become motile mesenchymal cells, occurs during development and marks a key step in tumour progression towards metastasis. Most studies of this process have focused on the disassembly of adherens junctions, but regulation of basement membrane breakdown by a pathway involving RhoA and microtubules may be equally important.

Epithelial cell death is highly prevalent during development and tissue homeostasis. While we have a rather good understanding of the molecular regulators of programmed cell death, especially for apoptosis, we still fail to predict when, where, how many and which specific cells will die in a tissue. This likely relies on the much more complex picture of apoptosis regulation in a tissular and epithelial context, which entails cell autonomous but also non-cell autonomous factors, diverse feedback and multiple layers of regulation of the commitment to apoptosis. In this review, we illustrate this complexity of epithelial apoptosis regulation by describing these different layers of control, all demonstrating that local cell death probability is a complex emerging feature. We first focus on non-cell autonomous factors that can locally modulate the rate of cell death, including cell competition, mechanical input and geometry as well as systemic effects. We then describe the multiple feedback mechanisms generated by cell death itself. We also outline the multiple layers of regulation of epithelial cell death, including the coordination of extrusion and regulation occurring downstream of effector caspases. Eventually, we propose a roadmap to reach a more predictive understanding of cell death regulation in an epithelial context. [ABSTRACT FROM AUTHOR]

Background: Quantitative imaging of epithelial tissues requires bioimage analysis tools that are widely applicable and accurate. In the case of imaging 3D tissues, a common preprocessing step consists of projecting the acquired 3D volume on a 2D plane mapping the tissue surface. While segmenting the tissue cells is amenable on 2D projections, it is still very difficult and cumbersome in 3D. However, for many specimen and models used in developmental and cell biology, the complex content of the image volume surrounding the epithelium in a tissue often reduces the visibility of the biological object in the projection, compromising its subsequent analysis. In addition, the projection may distort the geometry of the tissue and can lead to strong artifacts in the morphology measurement. Results: Here we introduce a user-friendly toolbox built to robustly project epithelia on their 2D surface from 3D volumes and to produce accurate morphology measurement corrected for the projection distortion, even for very curved tissues. Our toolbox is built upon two components. LocalZProjector is a configurable Fiji plugin that generates 2D projections and height-maps from potentially large 3D stacks (larger than 40 GB per time-point) by only incorporating signal of the planes with local highest variance/mean intensity, despite a possibly complex image content. DeProj is a MATLAB tool that generates correct morphology measurements by combining the height-map output (such as the one offered by LocalZProjector) and the results of a cell segmentation on the 2D projection, hence effectively deprojecting the 2D segmentation in 3D. In this paper, we demonstrate their effectiveness over a wide range of different biological samples. We then compare its performance and accuracy against similar existing tools. Conclusions: We find that LocalZProjector performs well even in situations where the volume to project also contains unwanted signal in other layers. We show that it can process large images without a pre-processing step. We study the impact of geometrical distortions on morphological measurements induced by the projection. We measured very large distortions which are then corrected by DeProj, providing accurate outputs. [ABSTRACT FROM AUTHOR]

The regulation of cell growth, cell proliferation and cell death is at the basis of the homeostasis of tissues. While they can be regulated by intrinsic and genetic factors, their response to external signals emanating from the local environment is also essential for tissue homeostasis. Tumour initiation and progression is based on the misregulation of growth, proliferation and death mostly through the accumulation of genetic mutations. Yet, there is an increasing body of evidences showing that tumour microenvironment also has a strong impact on cancer initiation and progression. This includes the mechanical constrains and the compressive forces generated by the resistance of the surrounding tissue/matrix to tumour expansion. Recently, mechanical stress has been proposed to promote competitive interactions between cells through a process called mechanical cell competition. Cell population with a high proliferative rate can compact and eliminate the neighbouring cells which are more sensitive to compaction. While this emerging concept has been recently validated in vivo , the relevance of this process during tumour progression has never been discussed extensively. In this review, I will first describe the phenomenology of mechanical cell competition focusing on the main parameters and the pathways regulating cell elimination. I will then discuss the relevance of mechanical cell competition in tumour initiation and expansion while emphasizing its potential opposing contributions to tumourogenesis. [ABSTRACT FROM AUTHOR]

Epithelial tissues are dramatically remodelled during embryogenesis and tissue homeostasis and yet need to maintain their sealing properties to sustain their barrier functions at any time. Part of these remodellings involve the elimination of a large proportion of cells through apoptosis. Cell extrusion, the remodelling steps leading to seamless dying cell expulsion, helps to maintain tissue cohesion. However, there is an intrinsic limit in the system that can only accommodate a certain proportion/rate of cell elimination as well as certain spatiotemporal distributions. What are then the critical conditions leading to epithelial rupture/tear/sealing defects upon cell elimination and which mechanisms ensure that such limits are never reached? In this short review, I document the conditions in which epithelial rupture has been observed, including in the contexts of epithelial cell death, and the mechanical parameters influencing tissue rupture, and review feedback mechanisms which help to keep the epithelia away from the breaking point. [ABSTRACT FROM AUTHOR]

The article offers information on a study on intercellular adhesion Regulation during epithelial morphogenesis. It informs that stable chemical and mechanical barriers are generated by epithelium between physiological compartments and can be remodeled during wound healing, embryogenesis and tumor progression. It also informs that relationship and the coupling in adhesive forces and cortical tension was studied in the study.

What regulates organ size and shape remains one fundamental mystery of modern biology. Research in this area has primarily focused on deciphering the regulation in time and space of growth and cell division, while the contribution of cell death has been overall neglected. This includes studies of the Drosophila wing, one of the best-characterized systems for the study of growth and patterning, undergoing massive growth during larval stage and important morphogenetic remodeling during pupal stage. So far, it has been assumed that cell death was relatively neglectable in this tissue both during larval stage and pupal stage, and as a result, the pattern of growth was usually attributed to the distribution of cell division. Here, using systematic mapping and registration combined with quantitative assessment of clone size and disappearance as well as live imaging, we outline a persistent pattern of cell death and clone elimination emerging in the larval wing disc and persisting during pupal wing morphogenesis. Local variation of cell death is associated with local variation of clone size, pointing to an impact of cell death on local growth that is not fully compensated by proliferation. Using morphometric analyses of adult wing shape and genetic perturbations, we provide evidence that patterned death locally and globally affects adult wing shape and size. This study describes a roadmap for precise assessment of the contribution of cell death to tissue shape and outlines an important instructive role of cell death in modulating quantitatively local growth and morphogenesis of a fast-growing tissue. [Display omitted] • Hotspots of apoptosis are present in Drosophila wing discs and pupal wings • These hotspots reduce net growth and increase clone disappearance locally • Patterned apoptosis has a significant impact on adult wing size and shape • Apoptosis fine-tunes organ shape and size even in the context of growth Matamoro-Vidal et al. use systematic and quantitative characterization of apoptosis in the Drosophila wing imaginal disc and pupal wing to reveal stereotyped spatial patterns of apoptosis that locally reduce growth, increase the probability of clone disappearance, and modulate adult wing shape and size. [ABSTRACT FROM AUTHOR]

Summary The plasticity of developing tissues relies on the adjustment of cell survival and growth rate to environmental cues. This includes the effect of mechanical cues on cell survival. Accordingly, compaction of an epithelium can lead to cell extrusion and cell death. This process was proposed to contribute to tissue homeostasis but also to facilitate the expansion of pretumoral cells through the compaction and elimination of the neighboring healthy cells. However, we know very little about the pathways that can trigger apoptosis upon tissue deformation, and the contribution of compaction-driven death to clone expansion has never been assessed in vivo. Using the Drosophila pupal notum and a new live sensor of ERK, we show first that tissue compaction induces cell elimination through the downregulation of epidermal growth factor receptor/extracellular signal regulated kinase (EGFR/ERK) pathway and the upregulation of the pro-apoptotic protein Hid. Those results suggest that the sensitivity of EGFR/ERK pathway to mechanics could play a more general role in the fine tuning of cell elimination during morphogenesis and tissue homeostasis. Second, we assessed in vivo the contribution of compaction-driven death to pretumoral cell expansion. We found that the activation of the oncogene Ras in clones can downregulate ERK and activate apoptosis in the neighboring cells through their compaction, which eventually contributes to Ras clone expansion. The mechanical modulation of EGFR/ERK during growth-mediated competition for space may contribute to tumor progression. Graphical Abstract Highlights • Caspase activity in Drosophila pupal notum is regulated by EGFR/ERK and hid • EGFR/ERK can be activated or downregulated by tissue stretching or compaction • Cell compaction near fast-growing clones downregulates ERK and triggers cell death • Compaction-driven ERK downregulation promotes fast-growing clone expansion Moreno et al. show that cell elimination in the Drosophila pupal notum can be locally adjusted by tissue deformation through the modulation of EGFR/ERK pathway and the pro-apoptotic gene hid. Compaction-driven ERK downregulation also occurs near fast-growing clones and promotes clone expansion through neighboring cell elimination. [ABSTRACT FROM AUTHOR]