-
Oncology Research 2021The Yes-associated protein (YAP) is a downstream effector of the Hippo pathway and acts as a key transcription co-factor to regulate cell migration, proliferation, and... (Review)
Review
The Yes-associated protein (YAP) is a downstream effector of the Hippo pathway and acts as a key transcription co-factor to regulate cell migration, proliferation, and survival. The Hippo pathway is evolutionarily conserved and controls tissue growth and organ size. Dysregulation and heterogeneity of this pathway are found in cancers, including oral squamous cell carcinoma (OSCC), leading to overexpression of YAP and its regulated proliferation machinery. The activity of YAP is associated with its nuclear expression and is negatively regulated by the Hippo kinase-mediated phosphorylation resulting in an induction of its cytoplasmic translocation. This review focuses on the role of YAP in OSCC in the context of cancer metastatic potential and highlights the latest findings about the heterogeneity of YAP expression and its nuclear transcription activity in oral cancer cell lines. The review also discusses the potential target of YAP in oral cancer therapy and the recent finding of the unprecedented role of the desmosomal cadherin desmoglein-3 (DSG3) in regulating Hippo-YAP signaling.
Topics: Humans; Mouth Neoplasms; Carcinoma, Squamous Cell; Transcription Factors; Squamous Cell Carcinoma of Head and Neck; Head and Neck Neoplasms
PubMed: 37304649
DOI: 10.32604/or.2022.026085 -
Gastroenterology Aug 2023Patients with colon cancer with liver metastases may be cured with surgery, but the presence of additional lung metastases often precludes curative treatment. Little is...
BACKGROUND & AIMS
Patients with colon cancer with liver metastases may be cured with surgery, but the presence of additional lung metastases often precludes curative treatment. Little is known about the processes driving lung metastasis. This study aimed to elucidate the mechanisms governing lung vs liver metastasis formation.
METHODS
Patient-derived organoid (PDO) cultures were established from colon tumors with distinct patterns of metastasis. Mouse models recapitulating metastatic organotropism were created by implanting PDOs into the cecum wall. Optical barcoding was applied to trace the origin and clonal composition of liver and lung metastases. RNA sequencing and immunohistochemistry were used to identify candidate determinants of metastatic organotropism. Genetic, pharmacologic, in vitro, and in vivo modeling strategies identified essential steps in lung metastasis formation. Validation was performed by analyzing patient-derived tissues.
RESULTS
Cecum transplantation of 3 distinct PDOs yielded models with distinct metastatic organotropism: liver only, lung only, and liver and lung. Liver metastases were seeded by single cells derived from select clones. Lung metastases were seeded by polyclonal clusters of tumor cells entering the lymphatic vasculature with very limited clonal selection. Lung-specific metastasis was associated with high expression of desmosome markers, including plakoglobin. Plakoglobin deletion abrogated tumor cell cluster formation, lymphatic invasion, and lung metastasis formation. Pharmacologic inhibition of lymphangiogenesis attenuated lung metastasis formation. Primary human colon, rectum, esophagus, and stomach tumors with lung metastases had a higher N-stage and more plakoglobin-expressing intra-lymphatic tumor cell clusters than those without lung metastases.
CONCLUSIONS
Lung and liver metastasis formation are fundamentally distinct processes with different evolutionary bottlenecks, seeding entities, and anatomic routing. Polyclonal lung metastases originate from plakoglobin-dependent tumor cell clusters entering the lymphatic vasculature at the primary tumor site.
Topics: Mice; Animals; Humans; gamma Catenin; Lung Neoplasms; Colonic Neoplasms; Liver Neoplasms
PubMed: 36906044
DOI: 10.1053/j.gastro.2023.02.047 -
Journal of Clinical Medicine Apr 2023Desmoplakin (DSP) is a desmosomal protein that plays an essential role for cell-to-cell adhesion within the cardiomyocytes. The first association between genetic... (Review)
Review
Desmoplakin (DSP) is a desmosomal protein that plays an essential role for cell-to-cell adhesion within the cardiomyocytes. The first association between genetic variants and the presence of a myocardial disease referred to patients with Carvajal syndrome. Since then, several reports have linked the gene to familial forms of arrhythmogenic (ACM) and dilated cardiomyopathies. Left-dominant ACM is the most common phenotype in individuals carrying variants. More recently, a new entity-"Desmoplakin cardiomyopathy"-was described as a distinct form of cardiomyopathy characterized by frequent left ventricular involvement with extensive fibrosis, high arrhythmic risk, and episodes of acute myocardial injury. The purpose of this review was to summarize the available evidence on DSP cardiomyopathy and to identify existing gaps in knowledge that need clarification from upcoming research.
PubMed: 37048743
DOI: 10.3390/jcm12072660 -
Dermatology Practical & Conceptual May 2022Autoimmune bullous diseases (AIBDs) are a group of skin-related disorders that involve damage to structures maintaining cell-cell adhesion, such as desmosomes and... (Review)
Review
Autoimmune bullous diseases (AIBDs) are a group of skin-related disorders that involve damage to structures maintaining cell-cell adhesion, such as desmosomes and hemidesmosomes. Key AIBDs include pemphigus related diseases, pemphigoid related conditions, acquired epidermolysis bullosa (EBA), and dermatitis herpetiformis (DH). Each group of conditions exhibits characteristic clinical lesion patterns and is associated with specific autoantibodies targeting epidermal and dermal structures involved in cell-cell adhesion and skin integrity. Pemphigus diseases primarily target desmoglein (Dsg) 3 and Dsg1 proteins but several non-Dsg autoantibodies have also been linked to pemphigus. Pemphigoid diseases typically target bullous pemphigoid (BP)180 and BP230; EBA is associated with antibodies directed against anti-type VII collagen and DH by IgA autoantibodies against tissue transglutaminase and deaminated gliadin. Investigation into the serological biomarkers found in AIBDs have allowed the development of diagnostic assessments (i.e. tissue antibody detection and serological testing) based on the unique autoantibody profiles of a particular disease group. The methods for the detection and quantification of disease-associated autoantibodies continue to evolve and improve.
PubMed: 35646449
DOI: 10.5826/dpc.1202a116 -
Life (Basel, Switzerland) Nov 2022The Hippo pathway is an evolutionarily conserved pathway that serves to promote cell death and differentiation while inhibiting cellular proliferation across species.... (Review)
Review
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.
PubMed: 36362947
DOI: 10.3390/life12111792 -
Frontiers in Oncology 2023Desmoglein-2 (DSG2) is a calcium-binding single pass transmembrane glycoprotein and a member of the large cadherin family. Until recently, DSG2 was thought to only... (Review)
Review
Desmoglein-2 (DSG2) is a calcium-binding single pass transmembrane glycoprotein and a member of the large cadherin family. Until recently, DSG2 was thought to only function as a cell adhesion protein embedded within desmosome junctions designed to enable cells to better tolerate mechanical stress. However, additional roles for DSG2 outside of desmosomes are continuing to emerge, particularly in cancer. Herein, we review the current literature on DSG2 in cancer and detail its impact on biological functions such as cell adhesion, proliferation, migration, invasion, intracellular signaling, extracellular vesicle release and vasculogenic mimicry. An increased understanding of the diverse repertoire of the biological functions of DSG2 holds promise to exploit this cell surface protein as a potential prognostic biomarker and/or target for better patient outcomes. This review explores the canonical and non-canonical functions of DSG2, as well as the context-dependent impacts of DSG2 in the realm of cancer.
PubMed: 38188287
DOI: 10.3389/fonc.2023.1327478 -
Genes Aug 2019The epithelium represents the first and most extensive line of defence against pathogens, toxins and pollutant agents in humans. In general, pathogens have developed... (Review)
Review
The epithelium represents the first and most extensive line of defence against pathogens, toxins and pollutant agents in humans. In general, pathogens have developed strategies to overcome this barrier and use it as an entrance to the organism. , and spp. are amoebae mainly responsible for intestinal dysentery, meningoencephalitis and keratitis, respectively. These amoebae cause significant morbidity and mortality rates. Thus, the identification, characterization and validation of molecules participating in host-parasite interactions can provide attractive targets to timely intervene disease progress. In this work, we present a compendium of the parasite adhesins, lectins, proteases, hydrolases, kinases, and others, that participate in key pathogenic events. Special focus is made for the analysis of assorted molecules and mechanisms involved in the interaction of the parasites with epithelial surface receptors, changes in epithelial junctional markers, implications on the barrier function, among others. This review allows the assessment of initial host-pathogen interaction, to correlate it to the potential of parasite invasion.
Topics: Acanthamoeba; Animals; Entamoeba histolytica; Epithelial Cells; Host-Parasite Interactions; Humans; Naegleria fowleri; Protozoan Infections
PubMed: 31416298
DOI: 10.3390/genes10080618 -
The keratin-desmosome scaffold of internal epithelia in health and disease - The plot is thickening.Current Opinion in Cell Biology Feb 2024Keratin (K) intermediate filaments are attached to desmosomes and constitute the orchestrators of epithelial cell and tissue architecture. While their relevance in the... (Review)
Review
Keratin (K) intermediate filaments are attached to desmosomes and constitute the orchestrators of epithelial cell and tissue architecture. While their relevance in the epidermis is well recognized, our review focuses on their emerging importance in internal epithelia. The significance of keratin-desmosome scaffolds (KDSs) in the intestine is highlighted by transgenic mouse models and individuals with inflammatory bowel disease who display profound KDS alterations. In lung, high K8 expression defines a transitional cell subset during regeneration, and K8 variants are associated with idiopathic pulmonary fibrosis. Inherited variants in desmosomal proteins are overrepresented in idiopathic lung fibrosis, and familiar eosinophilic esophagitis. K18 serum fragments are established hepatocellular injury markers that correlate with the extent of histological inflammation. K17 expression is modified in multiple tumors, and K17 levels might be of prognostic relevance. These data should spur further studies on biological roles of these versatile tissue protectors and efforts on their therapeutic targeting.
Topics: Mice; Animals; Keratins; Desmosomes; Cytoskeleton; Epithelium; Intermediate Filaments
PubMed: 38000362
DOI: 10.1016/j.ceb.2023.102282 -
Biomolecules Sep 2022Cell-cell junctions comprise various structures, including adherens junctions, tight junctions, desmosomes, and gap junctions. They link cells to each other in tissues... (Review)
Review
Cell-cell junctions comprise various structures, including adherens junctions, tight junctions, desmosomes, and gap junctions. They link cells to each other in tissues and regulate tissue homeostasis in critical cellular processes. Recent advances in cell-cell junction research have led to critical discoveries. Cell-cell adhesion components are important for the invasion and metastasis of tumour cells, which are not only related to cell-cell adhesion changes, but they are also involved in critical molecular signal pathways. They are of great significance, especially given that relevant molecular mechanisms are being discovered, there are an increasing number of emerging biomarkers, targeted therapies are becoming a future therapeutic concern, and there is an increased number of therapeutic agents undergoing clinical trials. Oesophageal squamous cell carcinoma (ESCC), the most common histological subtype of oesophageal cancer, is one of the most common cancers to affect epithelial tissue. ESCC progression is accompanied by the abnormal expression or localisation of components at cell-cell junctions. This review will discuss the recent scientific developments related to the molecules at cell-cell junctions and their role in ESCC to offer valuable insights for readers, provide a global view of the relationships between position, construction, and function, and give a reference for future mechanistic studies, diagnoses, and therapeutic developments.
Topics: Humans; Esophageal Squamous Cell Carcinoma; Adherens Junctions; Intercellular Junctions; Esophageal Neoplasms; Biomarkers
PubMed: 36291586
DOI: 10.3390/biom12101378 -
World Journal of Stem Cells Mar 2023Cardiomyopathy is a pathological condition characterized by cardiac pump failure due to myocardial dysfunction and the major cause of advanced heart failure requiring... (Review)
Review
Cardiomyopathy is a pathological condition characterized by cardiac pump failure due to myocardial dysfunction and the major cause of advanced heart failure requiring heart transplantation. Although optimized medical therapies have been developed for heart failure during the last few decades, some patients with cardiomyopathy exhibit advanced heart failure and are refractory to medical therapies. Desmosome, which is a dynamic cell-to-cell junctional component, maintains the structural integrity of heart tissues. Genetic mutations in desmosomal genes cause arrhythmogenic cardiomyopathy (AC), a rare inheritable disease, and predispose patients to sudden cardiac death and heart failure. Recent advances in sequencing technologies have elucidated the genetic basis of cardiomyopathies and revealed that desmosome-related cardiomyopathy is concealed in broad cardiomyopathies. Among desmosomal genes, mutations in (which encodes PKP2) are most frequently identified in patients with AC. deficiency causes various pathological cardiac phenotypes. Human cardiomyocytes differentiated from patient-derived induced pluripotent stem cells (iPSCs) in combination with genome editing, which allows the precise arrangement of the targeted genome, are powerful experimental tools for studying disease. This review summarizes the current issues associated with practical medicine for advanced heart failure and the recent advances in disease modeling using iPSC-derived cardiomyocytes targeting desmosome-related cardiomyopathy caused by deficiency.
PubMed: 37007457
DOI: 10.4252/wjsc.v15.i3.71