RESUMO
Balancing cell death and survival is essential for normal development and homeostasis and for preventing diseases, especially cancer. Conventional cell death pathways include apoptosis, a form of programmed cell death controlled by a well-defined biochemical pathway, and necrosis, the lysis of acutely injured cells. New types of regulated cell death include necroptosis, pyroptosis, ferroptosis, phagoptosis, and entosis. Autophagy can promote survival or can cause death. Newly described processes of anastasis and resuscitation show that, remarkably, cells can recover from the brink of apoptosis or necroptosis. Important new work shows that epithelia achieve homeostasis by extruding excess cells, which then die by anoikis due to loss of survival signals. This mechanically regulated process both maintains barrier function as cells die and matches rates of proliferation and death. In this review, we describe these unconventional ways in which cells have evolved to die or survive, as well as the contributions that these processes make to homeostasis and cancer.
Assuntos
Apoptose/genética , Autofagia/genética , Necrose/genética , Neoplasias/genética , Anoikis/genética , Proliferação de Células/genética , Entose/genética , Homeostase/genética , Humanos , Piroptose/genética , Transdução de Sinais/genéticaRESUMO
Cell extrusion is a mechanism of cell elimination that is used by organisms as diverse as sponges, nematodes, insects and mammals1-3. During extrusion, a cell detaches from a layer of surrounding cells while maintaining the continuity of that layer4. Vertebrate epithelial tissues primarily eliminate cells by extrusion, and the dysregulation of cell extrusion has been linked to epithelial diseases, including cancer1,5. The mechanisms that drive cell extrusion remain incompletely understood. Here, to analyse cell extrusion by Caenorhabditis elegans embryos3, we conducted a genome-wide RNA interference screen, identified multiple cell-cycle genes with S-phase-specific function, and performed live-imaging experiments to establish how those genes control extrusion. Extruding cells experience replication stress during S phase and activate a replication-stress response via homologues of ATR and CHK1. Preventing S-phase entry, inhibiting the replication-stress response, or allowing completion of the cell cycle blocked cell extrusion. Hydroxyurea-induced replication stress6,7 triggered ATR-CHK1- and p53-dependent cell extrusion from a mammalian epithelial monolayer. We conclude that cell extrusion induced by replication stress is conserved among animals and propose that this extrusion process is a primordial mechanism of cell elimination with a tumour-suppressive function in mammals.
Assuntos
Proteínas de Caenorhabditis elegans/genética , Proteínas de Ciclo Celular/genética , Replicação do DNA , Morte Celular Regulada , Fase S , Animais , Proteínas Mutadas de Ataxia Telangiectasia , Caenorhabditis elegans/citologia , Caenorhabditis elegans/genética , Pontos de Checagem do Ciclo Celular , Quinase 1 do Ponto de Checagem , Dano ao DNA , Cães , Embrião não Mamífero , Regulação da Expressão Gênica no Desenvolvimento , Células Madin Darby de Rim Canino , Interferência de RNARESUMO
To remove dying or unwanted cells from an epithelium while preserving the barrier function of the layer, epithelia use a unique process called cell extrusion. To extrude, the cell fated to die emits the lipid Sphingosine 1 Phosphate (S1P), which binds the G-protein-coupled receptor Sphingosine 1 Phosphate receptor 2 (S1P2) in the neighboring cells that activates Rho-mediated contraction of an actomyosin ring circumferentially and basally. This contraction acts to squeeze the cell out apically while drawing together neighboring cells and preventing any gaps to the epithelial barrier. Epithelia can extrude out cells targeted to die by apoptotic stimuli to repair the barrier in the face of death or extrude live cells to promote cell death when epithelial cells become too crowded. Indeed, because epithelial cells naturally turn over by cell death and division at some of the highest rates in the body, epithelia depend on crowding-induced live cell extrusion to preserve constant cell numbers. If extrusion is defective, epithelial cells rapidly lose contact inhibition and form masses. Additionally, because epithelia act as the first line of defense in innate immunity, preservation of this barrier is critical for preventing pathogens from invading the body. Given its role in controlling constant cell numbers and maintaining barrier function, a number of different pathologies can result when extrusion is disrupted. Here, we review mechanisms and signaling pathways that control epithelial extrusion and discuss how defects in these mechanisms can lead to multiple diseases. We also discuss tactics pathogens have devised to hijack the extrusion process to infect and colonize epithelia.
Assuntos
Proteína da Polipose Adenomatosa do Colo/metabolismo , Polipose Adenomatosa do Colo/metabolismo , Células Epiteliais/metabolismo , Lisofosfolipídeos/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Transdução de Sinais , Esfingosina/análogos & derivados , Polipose Adenomatosa do Colo/genética , Polipose Adenomatosa do Colo/patologia , Proteína da Polipose Adenomatosa do Colo/genética , Animais , Apoptose , Movimento Celular , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Células Epiteliais/patologia , Regulação da Expressão Gênica , Humanos , Listeria monocytogenes/patogenicidade , Listeria monocytogenes/fisiologia , Proteína Inibidora de Apoptose Neuronal/genética , Proteína Inibidora de Apoptose Neuronal/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Receptores de Lisoesfingolipídeo/genética , Salmonella typhimurium/patogenicidade , Salmonella typhimurium/fisiologia , Esfingosina/metabolismo , Receptores de Esfingosina-1-Fosfato , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Epithelia provide a crucial protective barrier for our organs and are also the sites where the majority of carcinomas form. Most studies on epithelia and carcinomas use cell culture or organisms where high-resolution live imaging is inaccessible without invasive techniques. Here, we introduce the developing zebrafish epidermis as an excellent in vivo model system for studying a living epithelium. We developed tools to fluorescently tag specific epithelial cell types and express genes in a mosaic fashion using five Gal4 lines identified from an enhancer trap screen. When crossed to a variety of UAS effector lines, we can now track, ablate or monitor single cells at sub-cellular resolution. Using photo-cleavable morpholino oligonucleotides that target gal4, we can also express genes in a mosaic fashion at specific times during development. Together, this system provides an excellent in vivo alternative to tissue culture cells, without the intrinsic concerns of culture conditions or transformation, and enables the investigation of distinct cell types within living epithelial tissues.
Assuntos
Técnicas Citológicas/métodos , Células Epidérmicas , Peixe-Zebra/metabolismo , Animais , Morte Celular/efeitos dos fármacos , Divisão Celular/efeitos dos fármacos , Cruzamentos Genéticos , Proteínas de Ligação a DNA/metabolismo , Elementos Facilitadores Genéticos/genética , Epiderme/efeitos dos fármacos , Epiderme/ultraestrutura , Células Epiteliais/citologia , Células Epiteliais/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Imageamento Tridimensional , Masculino , Morfolinos/farmacologia , Fatores de Tempo , Fatores de Transcrição/metabolismo , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
For an epithelium to provide a protective barrier, it must maintain homeostatic cell numbers by matching the number of dividing cells with the number of dying cells. Although compensatory cell division can be triggered by dying cells, it is unknown how cell death might relieve overcrowding due to proliferation. When we trigger apoptosis in epithelia, dying cells are extruded to preserve a functional barrier. Extrusion occurs by cells destined to die signalling to surrounding epithelial cells to contract an actomyosin ring that squeezes the dying cell out. However, it is not clear what drives cell death during normal homeostasis. Here we show in human, canine and zebrafish cells that overcrowding due to proliferation and migration induces extrusion of live cells to control epithelial cell numbers. Extrusion of live cells occurs at sites where the highest crowding occurs in vivo and can be induced by experimentally overcrowding monolayers in vitro. Like apoptotic cell extrusion, live cell extrusion resulting from overcrowding also requires sphingosine 1-phosphate signalling and Rho-kinase-dependent myosin contraction, but is distinguished by signalling through stretch-activated channels. Moreover, disruption of a stretch-activated channel, Piezo1, in zebrafish prevents extrusion and leads to the formation of epithelial cell masses. Our findings reveal that during homeostatic turnover, growth and division of epithelial cells on a confined substratum cause overcrowding that leads to their extrusion and consequent death owing to the loss of survival factors. These results suggest that live cell extrusion could be a tumour-suppressive mechanism that prevents the accumulation of excess epithelial cells.
Assuntos
Células Epiteliais/citologia , Homeostase , Nadadeiras de Animais/anatomia & histologia , Nadadeiras de Animais/citologia , Nadadeiras de Animais/embriologia , Animais , Apoptose , Contagem de Células , Morte Celular , Linhagem Celular , Movimento Celular , Proliferação de Células , Sobrevivência Celular , Colo/citologia , Cães , Embrião não Mamífero/citologia , Embrião não Mamífero/embriologia , Células Epidérmicas , Epiderme/embriologia , Humanos , Canais Iônicos/deficiência , Canais Iônicos/genética , Canais Iônicos/metabolismo , Lisofosfolipídeos/metabolismo , Modelos Biológicos , Neoplasias/patologia , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Peixe-Zebra/anatomia & histologia , Peixe-Zebra/embriologia , Proteínas de Peixe-Zebra/deficiência , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
Asthma is deemed an inflammatory disease, yet the defining diagnostic feature is mechanical bronchoconstriction. We previously discovered a conserved process called cell extrusion that drives homeostatic epithelial cell death when cells become too crowded. In this work, we show that the pathological crowding of a bronchoconstrictive attack causes so much epithelial cell extrusion that it damages the airways, resulting in inflammation and mucus secretion in both mice and humans. Although relaxing the airways with the rescue treatment albuterol did not affect these responses, inhibiting live cell extrusion signaling during bronchoconstriction prevented all these features. Our findings show that bronchoconstriction causes epithelial damage and inflammation by excess crowding-induced cell extrusion and suggest that blocking epithelial extrusion, instead of the ensuing downstream inflammation, could prevent the feed-forward asthma inflammatory cycle.
Assuntos
Asma , Brônquios , Broncoconstrição , Animais , Humanos , Camundongos , Asma/patologia , Asma/fisiopatologia , Broncoconstrição/efeitos dos fármacos , Inflamação/patologia , Transdução de Sinais , Canais Iônicos/antagonistas & inibidores , Lisofosfolipídeos/antagonistas & inibidores , Esfingosina/análogos & derivados , Esfingosina/antagonistas & inibidores , Brônquios/patologia , Brônquios/fisiopatologiaRESUMO
EGFR-ERK signaling controls cell cycle progression during development, homeostasis, and disease. While EGF ligand and mechanical inputs can activate EGFR-ERK signaling, the molecules linking mechanical force to this axis have remained mysterious. We previously found that stretch promotes mitosis via the stretch-activated ion channel Piezo1 and ERK signaling. Here, we show that Piezo1 provides the missing link between mechanical signals and EGFR-ERK activation. While both EGF- and Piezo1-dependent activation trigger clathrin-mediated EGFR endocytosis and ERK activation, EGF relies on canonical tyrosine autophosphorylation, whereas Piezo1 involves Src-p38 kinase-dependent serine phosphorylation. In addition, unlike EGF, ex vivo lung slices treated with Piezo1 agonist promoted cell cycle re-entry via nuclear ERK, AP-1 (FOS and JUN), and YAP accumulation, typical of regenerative and malignant signaling. Our results suggest that mechanical activation via Piezo1, Src, and p38 may be more relevant to controlling repair, regeneration, and cancer growth than tyrosine kinase signaling via canonical EGF signaling, suggesting an alternative therapeutic approach.
Assuntos
Fator de Crescimento Epidérmico , Transdução de Sinais , Fator de Crescimento Epidérmico/farmacologia , Quinases da Família src , Endocitose , Mitose , Receptores ErbBRESUMO
Epithelial cells work collectively to provide a protective barrier, yet also turn over rapidly by cell death and division. If the number of dying cells does not match those dividing, the barrier would vanish, or tumors can form. Mechanical forces and the stretch-activated ion channel (SAC) Piezo1 link both processes; stretch promotes cell division and crowding triggers cell death by initiating live cell extrusion1,2. However, it was not clear how particular cells within a crowded region are selected for extrusion. Here, we show that individual cells transiently shrink via water loss before they extrude. Artificially inducing cell shrinkage by increasing extracellular osmolarity is sufficient to induce cell extrusion. Pre-extrusion cell shrinkage requires the voltage-gated potassium channels Kv1.1 and Kv1.2 and the chloride channel SWELL1, upstream of Piezo1. Activation of these voltage-gated channels requires the mechano-sensitive Epithelial Sodium Channel, ENaC, acting as the earliest crowd-sensing step. Imaging with a voltage dye indicated that epithelial cells lose membrane potential as they become crowded and smaller, yet those selected for extrusion are markedly more depolarized than their neighbours. Loss of any of these channels in crowded conditions causes epithelial buckling, highlighting an important role for voltage and water regulation in controlling epithelial shape as well as extrusion. Thus, ENaC causes cells with similar membrane potentials to slowly shrink with compression but those with reduced membrane potentials to be eliminated by extrusion, suggesting a chief driver of cell death stems from insufficient energy to maintain cell membrane potential.
RESUMO
Asthma is deemed an inflammatory disease, yet the defining diagnostic symptom is mechanical bronchoconstriction. We previously discovered a conserved process that drives homeostatic epithelial cell death in response to mechanical cell crowding called cell extrusion(1, 2). Here, we show that the pathological crowding of a bronchoconstrictive attack causes so much epithelial cell extrusion that it damages the airways, resulting in inflammation and mucus secretion. While relaxing airways with the rescue treatment albuterol did not impact these responses, inhibiting live cell extrusion signaling during bronchoconstriction prevented all these symptoms. Our findings propose a new etiology for asthma, dependent on the mechanical crowding of a bronchoconstrictive attack. Our studies suggest that blocking epithelial extrusion, instead of ensuing downstream inflammation, could prevent the feed-forward asthma inflammatory cycle.
RESUMO
Introduction: Asthma is the most common chronic inflammatory disease of the airways. The airway epithelium is a key driver of the disease, and numerous studies have established genome-wide differences in mRNA expression between health and asthma. However, the underlying molecular mechanisms for such differences remain poorly understood. The human TTP family is comprised of ZFP36, ZFP36L1 and ZFP36L2, and has essential roles in immune regulation by determining the stability and translation of myriad mRNAs encoding for inflammatory mediators. We investigated the expression and possible role of the tristetraprolin (TTP) family of RNA binding proteins (RBPs), poorly understood in asthma. Methods: We analysed the levels of ZFP36, ZFP36L1 and ZFP36L2 mRNA in several publicly available asthma datasets, including single cell RNA-sequencing. We also interrogated the expression of known targets of these RBPs in asthma. We assessed the lung mRNA expression and cellular localization of Zfp36l1 and Zfp36l2 in precision cut lung slices in murine asthma models. Finally, we determined the expression in airway epithelium of ZFP36L1 and ZFP36L2 in human bronchial biopsies and performed rescue experiments in primary bronchial epithelium from patients with severe asthma. Results: We found ZFP36L1 and ZFP36L2 mRNA levels significantly downregulated in the airway epithelium of patients with very severe asthma in different cohorts (5 healthy vs. 8 severe asthma; 36 moderate asthma vs. 37 severe asthma on inhaled steroids vs. 26 severe asthma on oral corticoids). Integrating several datasets allowed us to infer that mRNAs potentially targeted by these RBPs are increased in severe asthma. Zfp36l1 was downregulated in the lung of a mouse model of asthma, and immunostaining of ex vivo lung slices with a dual antibody demonstrated that Zfp36l1/l2 nuclear localization was increased in the airway epithelium of an acute asthma mouse model, which was further enhanced in a chronic model. Immunostaining of human bronchial biopsies showed that airway epithelial cell staining of ZFP36L1 was decreased in severe asthma as compared with mild, while ZFP36L2 was upregulated. Restoring the levels of ZFP36L1 and ZFP36L2 in primary bronchial epithelial cells from patients with severe asthma decreased the mRNA expression of IL6, IL8 and CSF2. Discussion: We propose that the dysregulation of ZFP36L1/L2 levels as well as their subcellular mislocalization contributes to changes in mRNA expression and cytoplasmic fate in asthma.
RESUMO
Cells have developed diverse ways to separate two microtubule asters to form a mitotic spindle. Here, I focus on two mechanisms used to position asters around chromosomes during mitosis: first, aster migration around the nuclear envelope and, second, aster attachment to a contractile cortex at the plasma membrane after the nuclear envelope has broken down. Although certain cell types use one mechanism predominantly, most rely on both to ensure proper spindle assembly.
Assuntos
Fuso Acromático , Animais , Caenorhabditis elegans , Movimento Celular , Núcleo Celular/metabolismo , Centrossomo/ultraestrutura , Cromossomos/ultraestrutura , Citoplasma/metabolismo , Drosophila , Cinesinas/química , Mitose , Modelos BiológicosRESUMO
Epithelia remove dying or excess cells by extrusion, a process that seamlessly squeezes cells out of the layer without disrupting their barrier function. New studies shed light into the intricate relationship between extrusion, tissue mechanics, and development. They emphasize the importance of whole tissue-mechanics, rather than single cell-mechanics in controlling extrusion. Tissue compaction, stiffness, and cell-cell adhesion can impact the efficiency of cell extrusion and mechanisms that drive it, to adapt to different conditions during development or disease.
Assuntos
Apoptose , Células Epiteliais , EpitélioRESUMO
Metastasis is tightly linked with poor cancer prognosis, yet it is not clear how transformed cells become invasive carcinomas. We previously discovered that single KRasV12-transformed cells can invade directly from the epithelium by basal cell extrusion. During this process, cells de-differentiate by mechanically pinching off their epithelial determinants, but how they trans-differentiate into a migratory, mesenchymal phenotype is not known. Here, we demonstrate that basally extruded KRasV12-expressing cells become significantly deformed as they invade the zebrafish body. Decreasing the confinement that cells experience after they invade reduces the percentage of KRasV12 cells that trans-differentiate into mesenchymal cell types, while higher confinement increases this percentage. Additionally, increased confinement promotes accumulation of internal masses over time. Altogether, our results suggest that mechanical forces drive not only de-differentiation of KRasV12-transformed epithelial cells as they invade but also their re-differentiation into mesenchymal phenotypes that contribute to distant metastases.
RESUMO
Airway inflammation and remodelling are important pathophysiologic features in asthma and other respiratory conditions. An intact epithelial cell layer is crucial to maintain lung homoeostasis, and this depends on intercellular adhesion, whilst damaged respiratory epithelium is the primary instigator of airway inflammation. The Coxsackievirus Adenovirus Receptor (CAR) is highly expressed in the epithelium where it modulates cell-cell adhesion stability and facilitates immune cell transepithelial migration. However, the contribution of CAR to lung inflammation remains unclear. Here we investigate the mechanistic contribution of CAR in mediating responses to the common aeroallergen, House Dust Mite (HDM). We demonstrate that administration of HDM in mice lacking CAR in the respiratory epithelium leads to loss of peri-bronchial inflammatory cell infiltration, fewer goblet-cells and decreased pro-inflammatory cytokine release. In vitro analysis in human lung epithelial cells confirms that loss of CAR leads to reduced HDM-dependent inflammatory cytokine release and neutrophil migration. Epithelial CAR depletion also promoted smooth muscle cell proliferation mediated by GSK3ß and TGF-ß, basal matrix production and airway hyperresponsiveness. Our data demonstrate that CAR coordinates lung inflammation through a dual function in leucocyte recruitment and tissue remodelling and may represent an important target for future therapeutic development in inflammatory lung diseases.
Assuntos
Pneumonia , Pyroglyphidae , Receptores Virais , Animais , Humanos , Camundongos , Citocinas/metabolismo , Modelos Animais de Doenças , Inflamação/metabolismo , Pulmão/metabolismo , Pneumonia/metabolismo , Mucosa Respiratória/metabolismo , Receptores Virais/metabolismoRESUMO
Ezrin/radixin/moesin proteins link the actin cytoskeleton to the plasma membrane. Two new reports have found that moesin phosphorylation is essential for mitotic cell rounding and identify a new role for cell rounding in spindle assembly.
Assuntos
Forma Celular/fisiologia , Citoesqueleto/metabolismo , Proteínas de Drosophila/metabolismo , Proteínas de Membrana/metabolismo , Mitose/fisiologia , Proteínas Serina-Treonina Quinases/metabolismo , Actinas/metabolismo , Animais , Linhagem Celular , Citoesqueleto/fisiologia , Drosophila , FosforilaçãoRESUMO
Cellular extrusion is a mechanism that removes dying cells from epithelial tissues to prevent compromising their barrier function. Extrusion occurs in all observed epithelia in vivo and can be modeled in vitro by inducing apoptosis in cultured epithelial monolayers. We established that actin and myosin form a ring that contracts in the surrounding cells that drives cellular extrusion. It is not clear, however, if all apoptotic pathways lead to extrusion and how apoptosis and extrusion are molecularly linked. Here, we find that both intrinsic and extrinsic apoptotic pathways activate cellular extrusion. The contraction force that drives cellular extrusion requires caspase activity. Further, necrosis does not trigger the cellular extrusion response, but instead necrotic cells are removed from epithelia by a passive, stochastic movement of epithelial cells.
Assuntos
Apoptose/fisiologia , Células Epiteliais/fisiologia , Actinas/metabolismo , Animais , Apoptose/genética , Proteínas Reguladoras de Apoptose/metabolismo , Caspases/metabolismo , Linhagem Celular , Cães , Células Epiteliais/citologia , Humanos , Miosinas/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/genética , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Proteína X Associada a bcl-2/genética , Proteína X Associada a bcl-2/metabolismoRESUMO
Epithelial cells use the process of extrusion to promote cell death while preserving a tight barrier. To extrude, a cell and its neighbors contract actin and myosin circumferentially and basolaterally to seamlessly squeeze it out of the epithelium. Recent research highlights how early apical pulsatile contractions within the extruding cell might orchestrate contraction in three dimensions so that a cell extrudes out apically. Along with apical constrictions, studies of ion channels and mathematical modeling reveal how differential contraction between cells helps select specific cells to extrude. In addition, several studies have offered new insights into pathways that use extrusion to eliminate transformed cells or cause an aberrant form of extrusion that promotes cell invasion.
Assuntos
Neoplasias , Transdução de Sinais , Actinas/metabolismo , Células Epiteliais/metabolismo , Epitélio/metabolismo , HumanosRESUMO
Metastasis is the main cause of carcinoma-related death, yet we know little about how it initiates due to our inability to visualize stochastic invasion events. Classical models suggest that cells accumulate mutations that first drive formation of a primary mass, and then downregulate epithelia-specific genes to cause invasion and metastasis. Here, using transparent zebrafish epidermis to model simple epithelia, we can directly image invasion. We find that KRas-transformation, implicated in early carcinogenesis steps, directly drives cell invasion by hijacking a process epithelia normally use to promote death-cell extrusion. Cells invading by basal cell extrusion simultaneously pinch off their apical epithelial determinants, endowing new plasticity. Following invasion, cells divide, enter the bloodstream, and differentiate into stromal, neuronal-like, and other cell types. Yet, only invading KRasV12 cells deficient in p53 survive and form internal masses. Together, we demonstrate that KRas-transformation alone causes cell invasion and partial dedifferentiation, independently of mass formation.
Assuntos
Células Epiteliais/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Animais , Movimento Celular , Epiderme/metabolismo , Epitélio/metabolismo , Humanos , Neoplasias/diagnóstico por imagem , Peixe-Zebra/metabolismo , Proteínas de Peixe-ZebraRESUMO
Cell extrusion drives most epithelial cell death while maintaining a functional epithelial barrier. To extrude, a cell produces a lipid signal that triggers the neighboring cells to reorganize actin and myosin basally to squeeze the extruding cell out apically from the barrier. More studies continue to reveal other signals and mechanisms controlling apical extrusion. New developmental studies are uncovering mechanisms controlling basal extrusion, or ingression, which occurs when apical extrusion is defective or during de-differentiation in development. Here, we review recent advances in epithelial extrusion, focusing particularly on forces exerted upon extruding cells and their various later fates ranging from cell death, normal development, and cancer.
Assuntos
Células Epiteliais/citologia , Actinas/metabolismo , Animais , Fenômenos Biomecânicos , Doença , Células Epiteliais/metabolismo , Humanos , Miosinas/metabolismo , Sistema Nervoso/crescimento & desenvolvimentoRESUMO
When epithelia become too crowded, some cells are extruded that later die. To extrude, a cell produces the lipid, Sphingosine 1-Phosphate (S1P), which activates S1P2 receptors in neighboring cells that seamlessly squeeze the cell out of the epithelium. Here, we find that extrusion defects can contribute to carcinogenesis and tumor progression. Tumors or epithelia lacking S1P2 cannot extrude cells apically and instead form apoptotic-resistant masses, possess poor barrier function, and shift extrusion basally beneath the epithelium, providing a potential mechanism for cell invasion. Exogenous S1P2 expression is sufficient to rescue apical extrusion, cell death, and reduce orthotopic pancreatic tumors and their metastases. Focal Adhesion Kinase (FAK) inhibitor can bypass extrusion defects and could, therefore, target pancreatic, lung, and colon tumors that lack S1P2 without affecting wild-type tissue.