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Cell–cell adhesions are often subjected to mechanical strains of different rates and magnitudes in normal tissue function. However, the rate-dependent mechanical behavior of individual cell–cell adhesions has not been fully characterized due to the lack of proper experimental techniques and therefore remains elusive. This is particularly true under large strain conditions, which may potentially lead to cell–cell adhesion dissociation and ultimately tissue fracture. In this study, we designed and fabricated a single-cell adhesion micro tensile tester (SCAμTT) using two-photon polymerization and performed displacement-controlled tensile tests of individual pairs of adherent epithelial cells with a mature cell–cell adhesion. Straining the cytoskeleton–cell adhesion complex system reveals a passive shear-thinning viscoelastic behavior and a rate-dependent active stress-relaxation mechanism mediated by cytoskeleton growth. Under low strain rates, stress relaxation mediated by the cytoskeleton can effectively relax junctional stress buildup and prevent adhesion bond rupture. Cadherin bond dissociation also exhibits rate-dependent strengthening, in which increased strain rate results in elevated stress levels at which cadherin bonds fail. This bond dissociation becomes a synchronized catastrophic event that leads to junction fracture at high strain rates. Even at high strain rates, a single cell–cell junction displays a remarkable tensile strength to sustain a strain as much as 200% before complete junction rupture. Collectively, the platform and the biophysical understandings in this study are expected to build a foundation for the mechanistic investigation of the adaptive viscoelasticity of the cell–cell junction.

The relationship between the changes in endothelial cell–cell junctions and microvascular abnormalities in the progression of hypertrophic cardiomyopathy (HCM), as well as their potential as early biomarkers, remains unclear. Here, we analysed single‐nucleus RNA‐sequencing data from the left ventricles of 44 health donors and HCM patients. First, we observed that endothelial cell–cell junctions were significantly altered in HCM vascular endothelial cells (ECs), including tight junctions, gap junctions and adherens junctions, especially in capillary ECs. The proposed pseudo‐timing analysis predicted that endothelial cell–cell junctions abnormalities occurred in the early stages of HCM. Second, we verified that endothelial cell–cell junctions disorders occur at early stages of HCM disease progression in two time‐series single‐nucleus datasets of mice. The expression of eight cell–cell junction genes showed an initial increase in the early stage, followed by a slight decrease in the middle stage, and a sharp increase in the later stage. Subsequently, cell communication and transcription factor analysis were used to explore the underlying mechanisms. Furthermore, an early HCM prediction model was developed and independently validated using three mRNA datasets comprising 204 health individuals and HCM patients for the eight genes panel, the accuracy was 0.81 [0.63–0.98]. Finally, we validated this panel in HCM tissues. This study demonstrated in humans and mice that eight cell–cell junction genes were significantly elevated in the early stages of HCM and may be potential biomarkers for the early diagnosis of HCM.

Maintenance of cell junctions plays a crucial role in the regulation of cellular functions including cell proliferation, permeability, and cell death. Disruption of cell junctions is implicated in a variety of human disorders, such as inflammatory diseases and cancers. Understanding molecular regulation of cell junctions is important for development of therapeutic strategies for intervention of human diseases. Ubiquitination is an important type of post-translational modification that primarily regulates endogenous protein stability, receptor internalization, enzyme activity, and protein-protein interactions. Ubiquitination is tightly regulated by ubiquitin E3 ligases and can be reversed by deubiquitinating enzymes. Recent studies have been focusing on investigating the effect of protein stability in the regulation of cell-cell junctions. Ubiquitination and degradation of cadherins, claudins, and their interacting proteins are implicated in epithelial and endothelial barrier disruption. Recent studies have revealed that ubiquitination is involved in regulation of Rho GTPases' biological activities. Taken together these studies, ubiquitination plays a critical role in modulating cell junctions and motility. In this review, we will discuss the effects of ubiquitination and deubiquitination on protein stability and expression of key proteins in the cell-cell junctions, including junction proteins, their interacting proteins, and small Rho GTPases. We provide an overview of protein stability in modulation of epithelial and endothelial barrier integrity and introduce potential future search directions to better understand the effects of ubiquitination on human disorders caused by dysfunction of cell junctions.

Force transduction at cell-cell adhesions regulates tissue development, maintenance and adaptation. We developed computational and experimental approaches to quantify, with both sub-cellular and multi-cellular resolution, the dynamics of force transmission in cell clusters. Applying this technology to spontaneously-forming adherent epithelial cell clusters, we found that basal force fluctuations were coupled to E-cadherin localization at the level of individual cell-cell junctions. At the multi-cellular scale, cell-cell force exchange depended on the cell position within a cluster, and was adaptive to reconfigurations due to cell divisions or positional rearrangements. Importantly, force transmission through a cell required coordinated modulation of cell-matrix adhesion and actomyosin contractility in the cell and its neighbors. These data provide insights into mechanisms that could control mechanical stress homeostasis in dynamic epithelial tissues, and highlight our methods as a resource for the study of mechanotransduction in cell-cell adhesions. The intestines, liver, and skin are all examples of organs that perform specific functions. Organs are comprised of tissues, which are themselves made up of cells. Epithelial tissue is one of the four basic types of tissue found in animals, and it occurs in almost every organ in the body. For example, epithelial tissue makes up the outermost layer of the skin, and the lining of the lungs and the intestines; the cells in epithelial tissues are attached to one another via ‘adhesion molecules’. Organs and tissues need to be maintained throughout life in order for them to work properly. Epithelial cells in particular are very short-lived and must be constantly replaced. If epithelial tissue is cut or damaged in any way, the surrounding healthy epithelial cells must work together to repair the wound and restore the tissue's integrity. These processes require individual epithelial cells to communicate with one another. While chemical signals provide one means of cell-to-cell communication, cells also sense and respond to the physical presence of surrounding cells. In adults, organs and tissues generally do not change shape or size; as such there is a tightly balanced exchange of mechanical forces between the individual cells. Damage to the tissue causes a detectable change in these mechanical forces, which is sensed by nearby healthy epithelial cells and causes them to work towards healing the wound. While the importance of mechanical forces in maintaining tissue integrity is widely recognized, there were few tools to study these forces; this meant that mechanical communication through cell–cell adhesion sites was not well understood. Now Ng, Besser et al. describe the development and use of a new method for measuring and mapping the exchange of mechanical forces at cell–cell adhesion sites. Changes in the strength of the forces exchanged between cells could be measured across clusters of multiple cells or for specific parts of individual cells. Ng, Besser et al. found that when an epithelial cell in a cluster started to divide to form two new cells, the cell exerted less mechanical force on its neighboring cells. Ng, Besser et al. found that the forces exerted between cells were strongest when there was more of an adhesion molecule called E-cadherin in the cell surface membrane at the cell–cell adhesion sites. The opposite was also true, as these forces were weakest at cell–cell adhesion sites with fewer E-cadherin molecules. The new method and findings will now help to guide future studies into how mechanical forces are transmitted between living cells.

The Hippo pathway is an evolutionarily conserved pathway that serves to promote cell death and differentiation while inhibiting cellular proliferation across species. The downstream effectors of this pathway, yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ), are considered vital in promoting the output of the Hippo pathway, with activation of upstream kinases negatively regulating YAP/TAZ activity. The upstream regulation of the Hippo pathway is not entirely understood on a molecular level. However, several studies have shown that numerous cellular and non-cellular mechanisms such as cell polarity, contact inhibition, soluble factors, mechanical forces, and metabolism can convey external stimuli to the intracellular kinase cascade, promoting the activation of key components of the Hippo pathway and therefore regulating the subcellular localisation and protein activity of YAP/TAZ. This review will summarise what we have learnt about the role of intercellular junction-associated proteins in the activation of this pathway, including adherens junctions and tight junctions, and in particular our latest findings about the desmosomal components, including desmoglein-3 (DSG3), in the regulation of YAP signalling, phosphorylation, and subcellular translocation.

EpCAM (epithelial cell adhesion molecule) is a type I transmembrane glycoprotein, which was originally identified as a tumor-associated antigen due to its high expression level in rapidly growing epithelial tumors. Germ line mutations of the human EpCAM gene have been indicated as the cause of congenital tufting enteropathy. Previous studies based on cell models have revealed that EpCAM contributes to various biological processes including cell adhesion, signaling, migration and proliferation. Due to the previous lack of genetic animal models, the in vivo functions of EpCAM remain largely unknown. However, EpCAM genetic animal models have recently been generated, and are useful for understanding the functions of EpCAM. The authors here briefly review the functions and mechanisms of EpCAM in physiological processes and different diseases.

NF-κB transcription factors are critical regulators of innate and adaptive immunity and major mediators of inflammatory signaling. The NF-κB signaling is dysregulated in a significant number of cancers and drives malignant transformation through maintenance of constitutive pro-survival signaling and downregulation of apoptosis. Overactive NF-κB signaling results in overexpression of pro-inflammatory cytokines, chemokines and/or growth factors leading to accumulation of proliferative signals together with activation of innate and select adaptive immune cells. This state of chronic inflammation is now thought to be linked to induction of malignant transformation, angiogenesis, metastasis, subversion of adaptive immunity, and therapy resistance. Moreover, accumulating evidence indicates the involvement of NF-κB signaling in induction and maintenance of invasive phenotypes linked to epithelial to mesenchymal transition (EMT) and metastasis. In this review we summarize reported links of NF-κB signaling to sequential steps of transition from epithelial to mesenchymal phenotypes. Understanding the involvement of NF-κB in EMT regulation may contribute to formulating optimized therapeutic strategies in cancer. 2w--EZfHf_zRXWRyEmscJb Video Abstract

As the continuous development of the industrial revolution, nanomaterials with excellent characteristics have been widely applied in various fields, greatly increasing the probability of human exposure to nanomaterials and the concerns about the potential nanotoxicity. Existing studies have shown that the toxicity of nanomaterials may be closely related to oxidative stress, inflammatory response, phagocytosis dysfunction, DNA damage, etc. Based on our focus, nanomaterials may cross the human barrier through various channels and disrupt various cell-cell junctions, while the integrity of cellular barrier is a necessary for the normal physiological function of various organs. However, until now, there is still a lack of systematic discussion in this field. This review illustrates the importance of cell-cell junctions in maintaining various organ functions and highlights the mechanism of various nanomaterials disrupt cell-cell junctions, as well as the possible damage to various organs, such as brain, eye, lung, breast, intestine, placenta, testis, heart, liver, kidney, skin, etc. Awareness of the potential negative effects of nanomaterials will help scientists deeply understand the limitations of nanotechnology, inspiring them to develop safer and more efficient nanomaterials for future personalized nanomedicine.

Breast cancer undergoes collective tissue invasion and, in experimental models, can collectively metastasize. The prevalence of collective invasion and its contribution to distant metastasis in clinical disease, however, remains poorly defined. We here scored the adipose tissue invasion of primary invasive ductal carcinoma (IDC), expressing E-cadherin, and E-cadherin negative invasive lobular carcinoma (ILC) and identified predominantly collective invasion patterns (86/86 samples) in both carcinoma types. Whereas collective invasion in IDC lesions retained adherens junctions, multicellular clusters and “Indian files” in ILC, despite the absence of adherens junctions (AJ) proteins E-cadherin and β-catenin, retained CD44 at cell–cell contacts. By histomorphological scoring and semi-automated image analysis, we show that the extent of collective invasion into the adipose tissue correlated with decreased distant metastasis-free survival (5-year follow-up; hazard ratio: 2.32 and 2.29, respectively). Thus, collective invasion represents the predominant invasion mode in breast cancer, develops distinct junctional subtypes in IDC and ILC, and associates with distant metastasis, suggesting a critical role in systemic dissemination.

Helicobacter pylori produces outer membrane vesicles (OMV), delivering bacterial substances including the oncogenic cytotoxin-associated CagA protein to their surroundings. We investigated the effects of H. pylori OMV carrying CagA (OMV-CagA) on cell junctions and ATP-binding proteome of epithelial monolayers, using proteomics, mass spectrometry and imaging. OMV-CagA localized in close vicinity of ZO-1 tight junction protein and induced histone H1 binding to ATP. We suggest the expression of novel events in the interactions between H. pylori OMV and epithelia, which may have an influence on host gene transcription and lead to different outcomes of an infection and development of cancer. Distinct effects of Helicobacter pylori vesicles carrying oncoprotein CagA on human epithelial cells described here are useful for better understanding the outcomes of infection and development of cancer in the gut.