Death for life: a path from apoptotic signaling to tissue-scale effects of apoptotic epithelial extrusion

Gagliardi, Paolo Armando; Primo, Luca

doi:10.1007/s00018-019-03153-x

Cited by 11 publications

(6 citation statements)

References 64 publications

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“…Thus, the ESCRT-III complex may prevent excessive cell death by necroptosis (that involves permeabilization of the plasma membrane) in the context of renal transplantation (Gong et al, 2017). At the tissue scale, single epithelial cell loss in the intestinal or respiratory tract activates immediate closure of the gap by adjacent epithelial cells (Gagliardi and Primo, 2019), whereas removal of keratinocytes from the upper layer of the skin triggers rapid compensatory proliferation of cells in the basal level coupled with exudation of a microbicidal fluid. At the supracellular level, damage by local trauma such as cuts, frostbite, or burns gives rise to a rapid wound healing response designed to fill the breach, activating a stepwise series of responses including local inflammation with rapid recruitment of neutrophils and macrophages, capillary angiogenesis, and compensatory proliferation of fibroblasts and epithelial cells.…”

Section: Hallmark 2: Containment Of Local Perturbationsmentioning

confidence: 99%

Hallmarks of Health

López-Otı́n

Kroemer

2021

Cell

345

177

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Section: Hallmark 2: Containment Of Local Perturbationsmentioning

confidence: 99%

Hallmarks of Health

López-Otı́n

Kroemer

2021

Cell

345

177

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“…The orientation of cellular extrusion -either basally or apically depending on the model -can lead to either hypertrophic overgrowth (cancer) or apoptosis. Importantly, epithelial extrusion is a highly dynamic process in vivo, requiring coordination of the actin cytoskeleton and cell junction dis/assembly in cells fated to die as well as their neighbours to maintain tissue integrity (reviewed in Gagliardi and Primo, 2019). Intriguingly, mechanical stress due to crowding alone within a proliferating tissue is also sufficient to cause Caspase induction and basal delamination in the fly notum and may depend on the direction of cell division (Levayer et al, 2016;reviewed in Tada, 2021).…”

Section: Phosphorylated Erk Activation May Be a Mechanism For Cellular Extrusion In Notochord And Neural Cellsmentioning

confidence: 99%

JNK Mediates Differentiation, Cell Polarity and Apoptosis During Amphioxus Development by Regulating Actin Cytoskeleton Dynamics and ERK Signalling

Somorjai

Ehebauer

Escrivà

et al. 2021

Front. Cell Dev. Biol.

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c-Jun N-terminal kinase (JNK) is a multi-functional protein involved in a diverse array of context-dependent processes, including apoptosis, cell cycle regulation, adhesion, and differentiation. It is integral to several signalling cascades, notably downstream of non-canonical Wnt and mitogen activated protein kinase (MAPK) signalling pathways. As such, it is a key regulator of cellular behaviour and patterning during embryonic development across the animal kingdom. The cephalochordate amphioxus is an invertebrate chordate model system straddling the invertebrate to vertebrate transition and is thus ideally suited for comparative studies of morphogenesis. However, next to nothing is known about JNK signalling or cellular processes in this lineage. Pharmacological inhibition of JNK signalling using SP600125 during embryonic development arrests gastrula invagination and causes convergence extension-like defects in axial elongation, particularly of the notochord. Pharynx formation and anterior oral mesoderm derivatives like the preoral pit are also affected. This is accompanied by tissue-specific transcriptional changes, including reduced expression of six3/6 and wnt2 in the notochord, and ectopic wnt11 in neurulating embryos treated at late gastrula stages. Cellular delamination results in accumulation of cells in the gut cavity and a dorsal fin-like protrusion, followed by secondary Caspase-3-mediated apoptosis of polarity-deficient cells, a phenotype only partly rescued by co-culture with the pan-Caspase inhibitor Z-VAD-fmk. Ectopic activation of extracellular signal regulated kinase (ERK) signalling in the neighbours of extruded notochord and neural cells, possibly due to altered adhesive and tensile properties, as well as defects in cellular migration, may explain some phenotypes caused by JNK inhibition. Overall, this study supports conserved functions of JNK signalling in mediating the complex balance between cell survival, apoptosis, differentiation, and cell fate specification during cephalochordate morphogenesis.

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“…In crowded regions of the tissue, a proportion of cells experience a sustained loss of cell–cell junctions, while crowding induces neighboring cells to activate Rho-mediated assembly and contraction of intercellular actin-myosin rings, ultimately extruding the excessive live cells [ 6 , 7 ]. In normal situations, the extruded live cells eventually die through a process known as anoikis, or apoptosis due to loss of survival signaling [ 8 , 9 ]. Blood vessel epicardial substance (BVES), also known as Popeye domain-containing protein 1 (POPDC1), is firstly described as a three-pass transmembrane protein that localizes to the plasma membrane [ 10 ].…”

Section: Introductionmentioning

confidence: 99%

Cell adhesion molecule BVES functions as a suppressor of tumor cells extrusion in hepatocellular carcinoma metastasis

Han

Liu

et al. 2022

Cell Commun Signal

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Background Tumor cells detachment from primary lesions is an early event for hepatocellular carcinoma (HCC) metastasis, in which cell adhesion molecules play an important role. The role of mechanical crowding has attracted increasing attention. Previous studies have found that overcrowding can induce live cells extrusion to maintain epithelial cell homeostasis, and normally, live extruded cells eventually die through a process termed anoikis, suggesting the potential of tumor cells resistant to anoikis might initiate metastasis from primary tumors by cell extrusion. We have demonstrated transmembrane adhesion molecule blood vessel epicardial substance (BVES) suppression as an early event in HCC metastasis. However, whether its suppression is involved in HCC cell extrusion, especially in HCC metastasis, remains unknown. This study aims to investigate the role of BVES in tumor cells extrusion in HCC metastasis, as well as the underlying mechanisms. Methods Cells extrusion was observed by silicone chamber, petri dish inversion, and three-dimensional cell culture model. Polymerase chain reaction, western blotting, immunohistochemistry, immunofluorescence, co-immunoprecipitation, and RhoA activity assays were used to explore the underlying mechanisms of cell extrusion regulated by BVES. An orthotopic xenograft model was established to investigate the effects of BVES and cell extrusion in HCC metastasis in vivo. Results Tumor cell extrusion was observed in HCC cells and tissues. BVES expression was decreased both in HCC and extruded tumor cells. BVES overexpression led to the decrease in HCC cells extrusion in vitro and in vivo. Moreover, our data showed that BVES co-localized with ZO-1 and GEFT, regulating ZO-1 expression and localization, and GEFT distribution, thus modulating RhoA activity. Conclusion The present study revealed that BVES downregulation in HCC enhanced tumor cells extrusion, thus promoting HCC metastasis, which contributed to a more comprehensive understanding of tumor metastasis, and provided clues for developing novel HCC therapy strategies.

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Death for life: a path from apoptotic signaling to tissue-scale effects of apoptotic epithelial extrusion

Cited by 11 publications

References 64 publications

Hallmarks of Health

Hallmarks of Health

JNK Mediates Differentiation, Cell Polarity and Apoptosis During Amphioxus Development by Regulating Actin Cytoskeleton Dynamics and ERK Signalling

Cell adhesion molecule BVES functions as a suppressor of tumor cells extrusion in hepatocellular carcinoma metastasis

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