Competition for Space Is Controlled by Apoptosis-Induced Change of Local Epithelial Topology

Tsuboi, Alice; Ohsawa, Seiji; Umetsu, Daiki; Sando, Yukari; Kuranaga, Erina; Igaki, Tatsushi; Fujimoto, Koichi

doi:10.1016/j.cub.2018.05.029

Cited by 56 publications

(61 citation statements)

References 62 publications

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“…How tissues compete with each other for space is of great interest with many open biological questions being pursued in the experimental cell biology literature [5,21,45]. For example, in cancer invasion in an epithelial tissue a key question is whether cancer cells will eventually replace the entire healthy tissue or can the cancer cells coexist with the healthy cells?…”

Section: Mechanical Cell Competitionmentioning

confidence: 99%

Mechanical cell competition in heterogeneous epithelial tissues

Murphy

Buenzli

Baker

et al. 2019

Preprint

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Mechanical cell competition is important during tissue development, cancer invasion, and tissue ageing. Heterogeneity plays a key role in practical applications since cancer cells can have different cell stiffness and different proliferation rates than normal cells. To study this phenomenon, we propose a one-dimensional mechanical model of heterogeneous epithelial tissue dynamics that includes cell-length-dependent proliferation and death mechanisms. Proliferation and death are incorporated into the discrete model stochastically and arise as source/sink terms in the corresponding continuum model that we derive. Using the discrete model and the new continuum description, we explore several applications including the evolution of homogeneous tissues experiencing proliferation and death, and competition in a heterogeneous setting with a cancerous tissue competing for space with an adjacent normal tissue. This framework allows us to postulate new mechanisms that explain the ability of cancer cells to outcompete healthy cells through mechanical differences rather than by having some intrinsic proliferative advantage. 1In the emerging field of mechanical cell competition, winner cells compress neighbouring cells promoting tissue crowding and regions of higher density, which leads to cell death [5,21,47], while cell proliferation occurs in regions of lower density [13]. In this work, we focus on mechanical cell competition arising from the coupling of a cell-based model of epithelial tissue mechanics with celllength-dependent proliferation and death mechanisms. We consider mechanical forces to be driven by cell stiffness which is important for cancer progression [41], cancer detection [36], morphogenesis [10], and wound healing [9]. A grand challenge in cell biology is to understand how tissue-level outcomes are related to cell-based mechanisms, especially when experiments are performed by focusing on a single scale, and many cellular processes occur over multiple overlapping timescales [6,48]. Therefore, we apply mathematical modelling with in silico simulations to develop a framework to quantitatively connect cell-level mechanisms with tissue-level outcomes.Many mathematical modelling frameworks, including both discrete models and continuum models, have been used to study cell migration and cell proliferation. In discrete models individual cell properties and inter-cellular interactions can be prescribed [33,34]. However, discrete models often lack macroscopic intuition and can be computationally intensive, especially with proliferation and death included, which are commonly stochastic and require many realizations to understand the average behaviour. Continuum models commonly include proliferation and death through source/sink terms and may require constitutive equations to close the system [3,21,25,39,43]. In general, continuum models do not make the underlying cell-level processes clear [12]. However, continuum models can be less computationally expensive than discrete models and can be analysed with wellestablishe...

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Section: Mechanical Cell Competitionmentioning

confidence: 99%

Mechanical cell competition in heterogeneous epithelial tissues

Murphy

Buenzli

Baker

et al. 2019

Preprint

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“…6E ) and the expansion of the Ras V12 cell area which are close to the clone boundaries ( Fig. 6F, Ras V12 cell apical area near clone boundaries increased by 79% on average over 700min in controls, while only 24% for Ras V12 and sSpitz expressing cells), which are the cells that should compensate for most of the area left by the WT dying cells[37]. This suggested that cell elimination through ERK downregulation contributed to pretumoural clone expansion and global replacement of the WT cells.…”

Section: Resultsmentioning

confidence: 99%

Competition for space induces cell elimination through compaction-driven ERK downregulation

Moreno

Valon

Levillayer

et al. 2018

Preprint

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13The plasticity of developing tissues relies on the adjustment of cell survival and growth rate to 14 environmental cues. This includes the effect of mechanical cues on cell survival. Accordingly, 15 compaction of an epithelium can lead to cell extrusion and cell death. This process was 16proposed to contribute to tissue homeostasis but also to facilitate the expansion of pretumoral 17 cells through the compaction and elimination of the neighbouring healthy cells. However we 18 know very little about the pathways than can trigger apoptosis upon tissue deformation and 19 the contribution of compaction driven death to clone expansion was never assessed in vivo. 20Using the Drosophila pupal notum and a new live sensor of ERK, we show that tissue 21 compaction induces cell elimination through the downregulation of EGFR/ERK pathway and 22 the upregulation of the pro-apoptotic protein Hid. Those results suggest that the sensitivity of 23 EGFR/ERK pathway to mechanics could play a more general role in the fine tuning of cell 24 elimination during morphogenesis and tissue homeostasis. Secondly, we assessed in vivo the 25 contribution of compaction driven death to pretumoral cell expansion. We found that the 26 activation of the oncogene Ras in clones can also downregulate ERK and activate apoptosis 27 in the neighbouring cells through their compaction, which contributes to Ras clone expansion. 28The mechanical modulation of EGFR/ERK during growth-mediated competition for space may 29 contribute to tumour progression. 30 31 32 33Developing tissues have the capacity to cope with perturbations, which include stress from the 34 environment (mechanical, chemical, temperature) as well as abnormal behaviors of a subset 35 of cells (misspecification, local modification of growth rate). This robustness relies on the 36 plasticity of cell behavior/fate which can be adjusted to changes in the tissue environment. The 37 adjustment of cell proliferation and cell death could rely on several inputs, including contact 38 dependent communication, communication through extracellular diffusive factors and/or 39 communication through mechanical inputs [1]. Accordingly, mechanical cues have been 40proposed to adjust the local rate of cell death and cell division to regulate the final size of a 41 tissue or to maintain constant size during homeostasis [2][3][4]. 42The regulation of cell death by mechanical inputs is well documented in epithelia. Compaction 43 of epithelia was shown to induce cell extrusion and cell death in MDCK cells, and in the midline region of the Drosophila pupal notum (a single layer epithelium) [8] ( Fig. 45 1A). Recently, we showed that compaction driven cell elimination in the pupal notum relies on 46 caspase activation which was required for and preceding every extrusion event [9]. This 47 suggested that some unknown pathways could be sensitive to tissue deformations and trigger 48 caspase activation. However, we could not find a clear contribution of known 49 mechanosensitive pathways to midline cell eliminatio...

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“…Vertex models have been widely used in epithelial monolayer modelling including cell sorting [45], germband extension [46], ventral furrow formation [47], cell division and tissue elongation [48], wound healing [49,50], as well as tumor growth [51]. Vertex models have been used in studies of mechanical cell competition [34], as well as to infer the role of local epithelial topology on mutant clone expansion [23]. Vertex models, however, have some key disadvantages, including the difficulty to model arbitrary cell shapes, isolated cells, or cell clusters.…”

Section: Cell-based Modelsmentioning

confidence: 99%

Single-cell approaches to cell competition: High-throughput imaging, machine learning and simulations

Gradeci

Bove

Charras

et al. 2020

Seminars in Cancer Biology

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Cell competition is a quality control mechanism in tissues that results in the elimination of less fit cells. Over the past decade, the phenomenon of cell competition has been identified in many physiological and pathological contexts, driven either by biochemical signaling or by mechanical forces within the tissue. In both cases, competition has generally been characterized based on the elimination of loser cells at the population level, but significantly less attention has been focused on determining how single-cell dynamics and interactions regulate population-wide changes. In this review, we describe quantitative strategies and outline the outstanding challenges in understanding the single cell rules governing tissue-scale competition dynamics. We propose quantitative metrics to characterize single cell behaviors in competition and use them to distinguish the types and outcomes of competition. We describe how such metrics can be measured experimentally using a novel combination of high-throughput imaging and machine learning algorithms. We outline the experimental challenges to quantify cell fate dynamics with high-statistical precision, and describe the utility of computational modeling in testing hypotheses not easily accessible in experiments. In particular, cell-based modeling approaches that combine mechanical interaction of cells with decision-making rules for cell fate choices provide a powerful framework to understand and reverse-engineer the diverse rules of cell competition.

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Competition for Space Is Controlled by Apoptosis-Induced Change of Local Epithelial Topology

Cited by 56 publications

References 62 publications

Mechanical cell competition in heterogeneous epithelial tissues

Mechanical cell competition in heterogeneous epithelial tissues

Competition for space induces cell elimination through compaction-driven ERK downregulation

Single-cell approaches to cell competition: High-throughput imaging, machine learning and simulations

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