Distinct modes of cell competition shape mammalian tissue morphogenesis

Ellis, Stephanie J.; Gomez, Nicholas C.; Levorse, John; Mertz, Aaron F.; Ge, Yejing; Fuchs, Elaine

doi:10.1038/s41586-019-1199-y

Cited by 118 publications

(87 citation statements)

References 44 publications

(53 reference statements)

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“…Furthermore, our observation that mis-patterned and karyotypically abnormal cells show impaired mitochondrial activity indicates that during early mouse development different types of defects impair mitochondrial function and trigger cell competition. Interestingly, mtDNA genes are amongst the top mis-regulated factors identified during cell competition in the mouse skin (Ellis et al, 2019). In the Drosophila wing disc oxidative stress, a general consequence of dysfunctional mitochondria, underlies the out-competition of Minute and Mah-jong mutant cells (Kucinski et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development

Lima

Lubatti

Burgstaller

et al. 2020

Preprint

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Cell competition is emerging as a quality control mechanism that eliminates unfit cells in a wide range of settings from development to the adult. However, the nature of the cells normally eliminated by cell competition and what triggers their elimination remains poorly understood. Here we have performed single cell transcriptional profiling of early mouse embryos and find that the cells eliminated show the hallmarks of cell competition, are mis-patterned and have mitochondrial defects. We demonstrate that mitochondrial defects are common to a range of different loser cell types and that manipulating mitochondrial function is sufficient to trigger competition. Importantly, we show that in the embryo loser epiblast cells display mitochondrial DNA mutations and that even small changes in mitochondrial DNA sequence can influence the competitive ability of the cell.Our results therefore suggest that cell competition is a purifying selection that optimises metabolic output prior to gastrulation. Running title: Cell competition and mitochondrial selectionDuring the early stages of mammalian development, the cellular and molecular landscape is 2 profoundly remodelled. As embryonic cells approach gastrulation, when the precursors of all 3 embryonic tissues are specified, they need to rewire the transcriptional, epigenetic, metabolic and 4 signalling networks that govern cell identity (Kojima et al., 2014). These changes are accompanied 5 by a marked acceleration in the proliferation rate (Snow, 1977) and need to be orchestrated with 6 the different morphogenetic processes that re-shape the embryo (reviewed in (Stower and 7 Srinivas, 2018). The scale of this remodelling creates the potential for the emergence of abnormal 8 cells that need to be removed to prevent them from contributing to the soma or germline during 9 development. This requirement implies that there must be stringent cell fitness quality control 10 mechanisms acting around the time of gastrulation. One such control has been postulated to be 11 cell competition, a fitness sensing mechanism eliminating cells that, although viable, are less fit 12 than their neighbours (reviewed in (Bowling et al., 2019; Diaz-Diaz and Torres, 2019; Madan et 13 al., 2018). During cell competition, the cells that are eliminated are generically termed losers, while 14 the fitter cells that survive are referred to as winners. 15Cell competition has been primarily studied in Drosophila, where it was first described in the cell RNA sequencing (scRNA-seq). To ensure we can capture the eliminated cells, as we have 70 done before (Bowling et al., 2018), we isolated embryos at E5.5 and cultured them for 16 hours in 71 the presence of a caspase inhibitors (CI) or vehicle (DMSO) ( Figure 1A and Figure S1A). 72Unsupervised clustering of the scRNA-seq data revealed five clusters: two corresponding to extra-73 embryonic tissues (visceral endoderm and extra-embryonic ectoderm) and three that expressed 74 epiblast marker genes (Figure 1B-C and Figure S1B-D). Interestingly, cells from CI...

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Section: Discussionmentioning

confidence: 99%

Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development

Lima

Lubatti

Burgstaller

et al. 2020

Preprint

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“…It remains unclear how peridermal cells specifically recognize and target proliferating basal cells, as indicated by the drop of overall proliferation rates of p63-positive basal cells as a result of the extrusion process (Fig. 6 Q), and in contrast to cell competition wherein loser cells have a proliferative disadvantage (Ellis et al, 2019). Detachment of dividing basal cells from the basement membrane, possibly mediated by matrix metalloproteases, might be involved.…”

Section: Discussionmentioning

confidence: 99%

Entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of Matriptase

Armistead

Hatzold

Roye

et al. 2019

Journal of Cell Biology

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The type II transmembrane serine protease Matriptase 1 (ST14) is commonly known as an oncogene, yet it also plays an understudied role in suppressing carcinogenesis. This double face is evident in the embryonic epidermis of zebrafish loss-of-function mutants in the cognate Matriptase inhibitor Hai1a (Spint1a). Mutant embryos display epidermal hyperplasia, but also apical cell extrusions, during which extruding outer keratinocytes carry out an entosis-like engulfment and entrainment of underlying basal cells, constituting a tumor-suppressive effect. These counteracting Matriptase effects depend on EGFR and the newly identified mediator phospholipase D (PLD), which promotes both mTORC1-dependent cell proliferation and sphingosine-1-phosphate (S1P)–dependent entosis and apical cell extrusion. Accordingly, hypomorphic hai1a mutants heal spontaneously, while otherwise lethal hai1a amorphs are efficiently rescued upon cotreatment with PLD inhibitors and S1P. Together, our data elucidate the mechanisms underlying the double face of Matriptase function in vivo and reveal the potential use of combinatorial carcinoma treatments when such double-face mechanisms are involved.

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“…In drosophila, competitive recognition can involve secretion of JNK and NF-κB stimuli or juxtracrine comparison of cell surface proteins 39 . In mammalian tissues, high Myc cells force apoptosis, entosis, or differentiation of neighboring cells depending on the context 14-16 . We propose that the regulation of the ADAM17-EGFR paracrine signaling axis by MAPK signaling dynamics contributes to the recognition of distinct cell populations within tissues that leads to cellular competition.…”

Section: Discussionmentioning

confidence: 99%

Collective MAPK Signaling Dynamics Coordinates Epithelial Homeostasis

Aikin

Peterson

Pokrass

et al. 2019

Preprint

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12Epithelial tissues are constantly challenged by individual cell fate decisions while 13 maintaining barrier function. During oncogenesis, mutant and normal cells also differ in their 14 signaling states and cellular behaviors creating competitive interactions that are poorly 15 understood. Here we show that the temporal patterns of MAPK activity are decoded by the 16 ADAM17-EGFR paracrine signaling axis to coordinate migration of neighboring cells and promote 17 extrusion of aberrantly-signaling cells. Concurrently, neighboring cells increase proliferation to 18 maintain cell density while oncogene expressing cells undergo cell cycle arrest. Moreover, the 19 stress MAPK p38 elicits the same paracrine signaling and extrusion response, suggesting that 20 the ADAM17-EGFR pathway constitutes a quality control mechanism to eliminate and replace 21 unfit cells from epithelial tissues. Overall, we show that the temporal patterns of MAPK activity 22 coordinates both single and collective cell behaviors to maintain tissue homeostasis. 23 24 27 cancers 1 . In normal conditions the ERK pathway promotes proliferation, differentiation, survival 28 and cell migration 2 . Conversely, during oncogenesis mutations or amplification of ERK pathway 29 components can also promote oncogene-induced senescence 3 (OIS) or cellular extrusion from 30 epithelial monolayers 4,5 . The mechanisms underlying dose dependent effects of ERK signaling 31 have been intensely studied using bulk cell population assays. However, the advent of single cell 32 analysis has shown that single cells often behave qualitatively different than bulk populations. In 33 fact, in vivo and in vitro studies have now shown that pulsatile or sustained ERK activity have 34 different effects on cell fate 6-12 . Whether oncogenic perturbations also have different functional 35 outcomes depending on downstream signaling dynamics remains unknown. To address this 36 question, an isogenic single-cell approach with temporal control of oncogene expression is 37 needed. 38 39 Recent in vivo studies revealed that oncogene expression can trigger cell-cell competition and 40 tissue level responses involving normal neighboring cells 13-16 . During these events, the 41 mechanistic basis of competition and the signaling events involved in recognition between normal 42 and diseased cells are poorly understood. Coincidentally, propagating ERK signaling waves that 43 depend on the sheddase ADAM17 have been observed in mouse epidermis and intestinal 44 organoids, but the physiological role of these collective signaling events in homeostasis remains 45 unclear 7,8,17 . Understanding of the context-dependent mechanisms of paracrine signaling and cell-46 cell competition upon oncogene expression holds the key to unlocking new therapeutic strategies. 47 48 Here we combine live cell imaging of signaling biosensors with inducible expression of oncogenes 49 to study the cell autonomous and non-cell autonomous effects of oncogene expression in 50 epithelial monolayers. Our data shows that pulsa...

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Distinct modes of cell competition shape mammalian tissue morphogenesis

Cited by 118 publications

References 44 publications

Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development

Cell competition acts as a purifying selection to eliminate cells with mitochondrial defects during early mouse development

Entosis and apical cell extrusion constitute a tumor-suppressive mechanism downstream of Matriptase

Collective MAPK Signaling Dynamics Coordinates Epithelial Homeostasis

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