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    • br STAR Methods br Acknowledgments We are grateful to

    2019-09-23


    STAR★Methods
    Acknowledgments We are grateful to Amaia Lujambio, James Fagin, and Ramon Parsons for providing cell lines and Evripidis Gavathiotis for critical reading of the manuscript. We would like to thank Saboor Hekmaty for providing expertise with RNA-seq analysis. P.I.P. would like to acknowledge funding by the Dermatology Foundation, the Melanoma Research Foundation, the Melanoma Research Alliance, the Sidney Kimmel Foundation for Cancer Research, a TCI developmental award, and an NIH/NCI grant (R01CA204314). S.A.A. acknowledges a grant from the Breast Cancer Research Foundation. T.A.A. is supported by grant T32CA078207, and Z.K. would like to acknowledge the 2017 Robin Chemers Neustein Postdoctoral Fellowship.
    Introduction Developing tissues can cope with perturbations, including stress from the environment or abnormal behaviors of a subset of cells. This robustness relies on the plasticity of cell behavior and/or fate, which can adjust to changes in the tissue environment. Modulation of cell proliferation and cell death can be driven by contact-dependent communication, extracellular diffusive factors, and/or mechanical inputs [1]. Accordingly, mechanical cues have been proposed to adjust the local rate of cell death and cell division to regulate tissue final size or to maintain it during homeostasis [2, 3, 4]. The regulation of cell death by mechanical inputs is well documented in epithelia. Epithelial compaction can induce cell extrusion and cell death in MDCK cells, zebrafish epidermis [5, 6, 7], and in the midline region of the Drosophila pupal notum (a single layer epithelium; Figure 1A) [8]. Recently, we showed that compaction-driven cell elimination in the pupal notum relies on caspase activation, which is required for and precedes every extrusion event [9]. Thus, some pathways must be sensitive to tissue deformations and trigger and/or modulate caspase activation. However, we could not find a clear contribution of known mechanosensitive pathways to midline cell elimination, including p53 [7], the JNK pathway [10], or the Hippo Yap/Taz pathway [9, 11]. Moreover, it also suggested that AS1842856 clinical could have differential sensitivity to compaction depending on their sensitivity to apoptosis. Accordingly, activation of Ras in clones led to the preferential compaction and elimination of the neighboring wild-type (WT) cells [9]. Similarly, the high levels of p53 in mutant MDCK cells for the polarity gene scribble increase their sensitivity to compaction and trigger their elimination when surrounded by WT MDCK cells [7, 12]. Those eliminations have been proposed to promote the expansion of pretumoral cells through a so-called mechanical cell competition [7, 9, 13, 14]. However, the molecular pathway triggering cell death during mechanical cell competition in vivo was not yet identified, and it was not yet clear whether such elimination could significantly promote pretumoral clone expansion. Here, we show that tissue compaction induces cell elimination in the pupal notum through the downregulation of epidermal growth factor receptor/extracellular signal regulated kinase (EGFR/ERK) pathway and the upregulation of the pro-apoptotic protein Hid (head involution defective). Using a new Drosophila live sensor of ERK activity, we demonstrate that local tissue stretching or compaction transiently upregulate or downregulate ERK activity, hence increasing or decreasing cell survival. Moreover, we show that compaction-driven ERK downregulation near Ras-activated clones controls cell elimination and promotes clone expansion. The sensitivity of EGFR/ERK pathway to mechanics and its role in the fine tuning of cell elimination could play a more general role during tissue homeostasis and tumor progression.
    Results
    Discussion EGFR/ERK/Hid pathway has been previously involved in tissue homeostasis and cell number regulation [44, 45]. For instance, modulation of segment size in Drosophila embryo can be adjusted by cell death regulated by EGFR/Hid and the limited source of Spitz/EGF [45, 46]. A similar mechanism is involved in the regulation of the number of interommatidial cells in the fly retina [19, 47, 48, 49, 50] or the number of glia cells in the embryo [51]. Those studies are based on the modulation of EGFR/ERK and death triggered by limiting extracellular ligands. Here, we show that ERK activity can also be modified by tissue mechanics in vivo, which changes the probability of cell survival. Modulation of ERK activity by mechanical stress and/or tissue density has been previously described in cell culture [31, 33, 34, 36, 52] and in vivo [35]. Here, we provide the first evidence of a mechanical modulation of ERK playing an instructive role for cell survival and death during competitive interactions between two cell types in vivo. So far, most of the studies of mechanotransduction in vivo focused on the regulation of Hippo/Yap-Taz pathway [11], whose transcriptional outputs should act on hours timescale. Our results suggest that ERK modulation could act on cell survival in a few tens of minutes (see Figure 4) through the phosphorylation [18] and/or transcriptional regulation [19] of Hid.