Competition for Space Induces Cell Elimination through Compaction-Driven ERK Downregulation

Abstract

SummaryThe 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.

Dying under pressure: cellular characterisation and in vivo functions of cell death induced by compaction

“…Similarly, the local rate of cell death in the Drosophila pupal notum correlates with the local rate of compaction (measured by Particle Image Velocimetry) rather than absolute tissue density, suggesting that cell survival is modulated by strain rate and/or forces [Levayer et al, 2016]. The sensing of deformations is triggered through the modulation of ERK activity which will impact cell survival via the inhibition of the pro-apoptotic protein Hid [Moreno et al, 2018]. Those results are in agreement with the previous reports of ERK activation by cellular tension in cell culture [Tschumperlin et al, 2004, Aoki et al, 2013, Hirata et al, 2015, Kawabata and Matsuda, 2016, Aoki et al, 2017 and in vivo [Sano et al, 2016].…”

Mechanical competition triggered by innate immune signaling drives the collective extrusion of bacterially-infected epithelial cells

“…Signaling pathways suggested to be involved in mechanical cellular hypersensitivity include ROCK-mediated contractility 35 and myosin II activity 39 , mTOR-p70S6K signaling, abundant winner cell vimentin and filamin expression 40,41 , the HIPPO pathway and compaction driven EGF-MEK-ERK signaling 39,42 . However how exactly signaling is linked to cytoskeletal and mechanical changes in competing cells and which factors cause mounding as opposed to resulting from mounding is still unclear and potentially multi-factorial.…”

Local retinoic acid directs emergence of the extraocular muscle functional unit

“…Although our work sheds light on the genetic mechanisms that regulate EOM insertion, the cellular mechanisms underlying this process remains undefined. It is tempting to speculate that the apoptotic foci are related to the disappearance of signaling centers (Jernvall et al, 1998;Nonomura et al, 2013) or compaction-mediated cell death and extrusion (Moreno et al, 2019). Future experiments directed towards modifying the amount or timing of cell death will be informative.…”