EphA2 Drives the Segregation of Ras-Transformed Epithelial Cells from Normal Neighbors

Porazinski, Sean; Navascués, Joaquı́n; Yako, Yuta; Hill, William; Jones, Matthew R.; Maddison, Robert; Fujita, Yasuyuki; Hogan, Catherine

doi:10.1016/j.cub.2016.09.037

Cited by 74 publications

(123 citation statements)

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“…Cell-cell communication mechanisms may therefore be broadly conserved between neuroepithelial progeny, with typically repulsive axon-guidance genes functioning in epithelia to extrude aberrant cells. Indeed, alongside Slit-Robo, ephrin-A-EphA2 signaling repels and extrudes Ras V12 cells in MDCK monolayers and wing discs (Porazinski et al, 2016), and repulsive Semaphorin-Plexin signaling removes damaged cells by basal extrusion during JNK-dependent wound healing in wing discs (Yoo et al, 2016). As JNK signaling is required for diverse phenomena that include cell extrusion, such as cell competition and wound healing, downstream signals like Slit-Robo and subsequent junctional dissolution may more broadly mediate cell extrusion and regulate epithelial homeostasis.…”

Section: Cell Competition and The Active Extrusion Of Aberrant Cellsmentioning

confidence: 99%

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

2018

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Epithelial tissues robustly respond to internal and external stressors via dynamic cellular rearrangements. Cell extrusion acts as a key regulator of epithelial homeostasis by removing apoptotic cells, orchestrating morphogenesis, and mediating competitive cellular battles during tumorigenesis. Here, we delineate the diverse functions of cell extrusion during development and disease. We emphasize the expanding role for apoptotic cell extrusion in exerting morphogenetic forces, as well as the strong intersection of cell extrusion with cell competition, a homeostatic mechanism that eliminates aberrant or unfit cells. While cell competition and extrusion can exert potent, tumor-suppressive effects, dysregulation of either critical homeostatic program can fuel cancer progression.

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Section: Cell Competition and The Active Extrusion Of Aberrant Cellsmentioning

confidence: 99%

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

2018

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“…This suppression of the wild-type cells' growth was density-dependent ( Figure 2C) The increased loss of wild-type cells which we observed upon increasing the 157 ratio of variant cells in co-cultures, or upon plating the co-cultures at increasing cell 158 densities, could be explained by two possibilities: either the higher numbers of wild-159 type-variant heterotypic cell contacts result in receptor-mediated cell competition 160 (Burke and Basler, 1996), or alternatively, the winner cells are mechanically 161 compressing the losers causing their eradication from cultures in a process termed 162 mechanical cell competition (Levayer et al, 2016;Wagstaff et al, 2016). To distinguish 163 between these possibilities, we first performed a cell confrontation assay, which allows 164 two cell populations to be brought into contact at a clearly defined border (Moitrier et 165 al., 2019;Porazinski et al, 2016). We reasoned that the receptor-mediated competition 166 would result in cell apoptosis localised at the border of heterotypic cell contacts, 167 whereas mechanical cell competition would result in the apoptotic signal spread 168 throughout the areas of cell crowding (Bras-Pereira and Moreno, 2018).…”

Section: Crowding Of Loser Cells Within Mosaic Cultures Induces Losermentioning

confidence: 99%

Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition

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Stavish

Gokhale

et al. 2019

Preprint

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21The appearance of genetic changes in human pluripotent stem cells (hPSCs) presents a 22 concern for their use in research and regenerative medicine. Variant hPSCs harbouring 23 recurrent culture-acquired aneuploidies display growth advantages over wild-type 24 diploid cells, but the mechanisms yielding a drift from predominantly wild-type to 25 variant cell populations remain poorly understood. Here we show that the dominance 26 of variant clones in mosaic cultures is enhanced through competitive interactions 27 resulting in elimination of wild-type cells. This elimination occurs through corralling 28 and mechanical compression by faster growing variants, causing a redistribution of F-29 actin and sequestration of YAP in the cytoplasm that induces apoptosis in wild-type 30 cells. Importantly, YAP overexpression in wild-type cells is sufficient to alleviate their 31 loser phenotype. Our results demonstrate that hPSC fate is coupled to mechanical cues 32 imposed by neighbouring cells and reveal that hijacking this mechanism allows variants 33 to achieve clonal dominance in cultures. 34 35 Keywords: human pluripotent stem cells, culture acquired variants, cell competition, 36 YAP 37 38 wild-type cells in mosaic cultures, akin to the super-competition-like behaviour 89 described in other cell types (de la Cova et al., 2004; Moreno and Basler, 2004). The 90 elimination of loser cells in hPSC cultures is exerted through mechanical cues, and is 91 mediated by YAP, downstream of the actomyosin cytoskeleton. Our findings illuminate 92 the reliance of hPSC fates on their mechanical environment and highlight the need for 93 consideration of culture space limitations in the scale up of hPSCs for research or 94 clinical use. 95 96 6 Results 97 Variant hPSCs selectively eliminate diploid wild-type counterparts from co-98 cultures 99 To uncover the reasons behind the rapid overtake of cultures by genetically variant 100 hPSCs (Olariu et al., 2010), we sought to examine how wild-type and genetically 101 variant hPSCs interact and whether they affect each other's growth. To this end, we 102 initially used two diploid H7 sublines (either non-modified or genetically engineered to 103 constitutively express red fluorescent protein (RFP), termed wild-type and wild-type-104 RFP, respectively), and their aneuploid variant harbouring a gain of chromosomes 1, 105 12, 17q and 20q CNV, and stably expressing green fluorescent protein (GFP) (termed 106 variant-GFP). Time-lapse microscopy of co-cultures containing wild-type-RFP and 107variant-GFP cells showed a selective elimination of wild-type-RFP cells during a three-108 day culture period (Video S1). To establish that the observed elimination is due to the 109 presence of variant cells in mixed cultures we compared the growth rates of wild-type-110 RFP or unlabelled wild-type cells in separate culture to how they grew in mixed cultures 111 with variant-GFP cells. Wild-type sublines were viable and created well-established, 112 large colonies in separate culture, but consistent with prev...

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“…In this work, we investigate the mechanisms of competitive cell interactions between normal and precancerous Human Embryonic Kidney (HEK) cell assemblies. In particular, we assess the invasive capacity of oncogene-bearing cells by adapting the classical wound healing assay [19] to an antagonistic migration assay (AMA) of two cell populations [11,12,13,14]. This approach holds the advantage of creating an interface between two cell populations in a reproducible way.…”

Section: Introductionmentioning

confidence: 99%

Collective stresses drive competition between monolayers of normal and Ras-transformed cells

et al. 2019

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We study the competition for space between two cell lines that differ only in the expression of the Ras oncogene. The two cell populations are initially separated and set to migrate antagonistically towards an in-between stripe of free substrate. After contact, their interface moves towards the population of normal cells. We interpret the velocity and traction force data taken before and after contact thanks to a hydrodynamic description of collectively migrating cohesive cell sheets. The kinematics of cells, before and after contact, allows us to estimate the relative material parameters for both cell lines. As predicted by the model, the transformed cell population with larger collective stresses pushes the wild type cell population.

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EphA2 Drives the Segregation of Ras-Transformed Epithelial Cells from Normal Neighbors

Cited by 74 publications

References 40 publications

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

Cell Extrusion: A Stress-Responsive Force for Good or Evil in Epithelial Homeostasis

Genetically variant human pluripotent stem cells selectively eliminate wild-type counterparts through YAP-mediated cell competition

Collective stresses drive competition between monolayers of normal and Ras-transformed cells

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