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BackgroundThe clinical phenotype of CDH1 pathogenic variant carriers has mostly been studied in families that fulfil criteria of hereditary diffuse gastric cancer (HDGC). We aimed at determining cancer phenotype and cancer risk estimation among families with CDH1 pathogenic variants not selected by HDGC clinical criteria.MethodsPatients were all consecutively identified CDH1 pathogenic variant carriers from a clinical laboratory tested with multigene panel testing and from an academic cancer genetics programme. Clinical and demographic features, cancer phenotypes and genotype–phenotype correlations were determined among CDH1 families. Age-specific cumulative cancer risks (penetrance) were calculated based on 38 families with available pedigrees.ResultsWithin the 113 CDH1 pathogenic variant probands and 476 relatives, 113 had gastric cancer, 177 breast cancer and 196 other cancers. Mean age at diagnosis was 47 for gastric and 54 for breast cancer. Forty-six per cent fulfilled criteria of HDGC. While 36% of families had both gastric and breast cancers, 36% had breast but no gastric cancers and 16% had gastric but not breast cancers. Cumulative risk of cancer by age 80 was 37.2% for gastric and 42.9% for breast cancer.ConclusionIn unselected CDH1 pathogenic variant carrier families, gastric cancer risks were lower and age at diagnosis higher than previously reported in families pre-selected for HDGC criteria. A substantial proportion of families did not present with any gastric cancers and their cancers were limited to breast. Thus, clinical criteria for CDH1 testing should be widened, including breast cancer families only, and a consideration for delayed prophylactic gastrectomy/surveillance should be evaluated.

The ubiquitination of cell cycle regulatory proteins by the anaphase-promoting complex/cyclosome (APC/C) controls sister chromatid segregation, cytokinesis and the establishment of the G1 phase of the cell cycle. The APC/C is an unusually large multimeric cullin-RING ligase. Its activity is strictly dependent on regulatory coactivator subunits that promote APC/C–substrate interactions and stimulate its catalytic reaction. Because the structures of many APC/C subunits and their organization within the assembly are unknown, the molecular basis for these processes is poorly understood. Here, from a cryo-electron microscopy reconstruction of a human APC/C–coactivator–substrate complex at 7.4 Å resolution, we have determined the complete secondary structural architecture of the complex. With this information we identified protein folds for structurally uncharacterized subunits, and the definitive location of all 20 APC/C subunits within the 1.2 MDa assembly. Comparison with apo APC/C shows that the coactivator promotes a profound allosteric transition involving displacement of the cullin-RING catalytic subunits relative to the degron-recognition module of coactivator and APC10. This transition is accompanied by increased flexibility of the cullin-RING subunits and enhanced affinity for UBCH10–ubiquitin, changes which may contribute to coactivator-mediated stimulation of APC/C E3 ligase activity. The anaphase-promoting complex/cyclosome (APC/C) is a large E3 ligase that mediates ubiquitin-dependent proteolysis of cell cycle regulatory proteins; here the complete secondary structure architecture of human APC/C complexed with its coactivator CDH1 and substrate HSL1 is determined at 7.4 Å resolution, revealing allosteric changes induced by the coactivator that enhance affinity for UBCH10–ubiqutin. Human anaphase-promoting complex structure The anaphase-promoting complex/cyclosome (APC/C) is a large E3 ligase that mediates ubiquitin-dependent proteolysis of cell cycle regulatory proteins to control various events during replication and cell division. Here, using cryo-electron microscopy, David Barford and colleagues determine the complete secondary structural architecture of human APC/C in complex with its coactivator CDH1 and substrate HSL1 at 7.4 Å resolution. The structural information allows the position and architecture of all 20 APC/C subunits to be defined and provides insights into how CDH1 stimulates APC/C ubiquitination activity.

Mammalian cells integrate mitogen and stress signalling before the end of G1 phase to determine whether or not they enter the cell cycle . Before cells can replicate their DNA in S phase, they have to activate cyclin-dependent kinases (CDKs), induce an E2F transcription program and inactivate the anaphase-promoting complex (APC/C , also known as the cyclosome), which is an E3 ubiquitin ligase that contains the co-activator CDH1 (also known as FZR, encoded by FZR1). It was recently shown that stress can return cells to quiescence after CDK2 activation and E2F induction but not after inactivation of APC/C , which suggests that APC/C inactivation is the point of no return for cell-cycle entry . Rapid inactivation of APC/C requires early mitotic inhibitor 1 (EMI1) , but the molecular mechanism that controls this cell-cycle commitment step is unknown. Here we show using human cell models that cell-cycle commitment is mediated by an EMI1-APC/C dual-negative feedback switch, in which EMI1 is both a substrate and an inhibitor of APC/C . The inactivation switch triggers a transition between a state with low EMI1 levels and high APC/C activity during G1 and a state with high EMI1 levels and low APC/C activity during S and G2. Cell-based analysis, in vitro reconstitution and modelling data show that the underlying dual-negative feedback is bistable and represents a robust irreversible switch. Our study suggests that mammalian cells commit to the cell cycle by increasing CDK2 activity and EMI1 mRNA expression to trigger a one-way APC/C inactivation switch that is mediated by EMI1 transitioning from acting as a substrate of APC/C to being an inhibitor of APC/C .

Mammalian embryos initiate morphogenesis with compaction, which is essential for specifying the first lineages of the blastocyst. The 8-cell-stage mouse embryo compacts by enlarging its cell–cell contacts in a Cdh1-dependent manner. It was therefore proposed that Cdh1 adhesion molecules generate the forces driving compaction. Using micropipette aspiration to map all tensions in a developing embryo, we show that compaction is primarily driven by a twofold increase in tension at the cell–medium interface. We show that the principal force generator of compaction is the actomyosin cortex, which gives rise to pulsed contractions starting at the 8-cell stage. Remarkably, contractions emerge as periodic cortical waves when cells are disengaged from adhesive contacts. In line with this, tension mapping of mzCdh1 −/− embryos suggests that Cdh1 acts by redirecting contractility away from cell–cell contacts. Our study provides a framework to understand early mammalian embryogenesis and original perspectives on evolutionary conserved pulsed contractions. By measuring surface tensions in developing mouse embryos, Maître and colleagues show that compaction of the blastomere stage embryo is driven by downregulation of actomyosin at cell–cell contacts.

E-cadherin, encoded by the CDH1 gene, plays an essential role in epithelial cellular adhesion, and the loss of it has been reported to be associated with tumor progression and metastasis, potentially offer a glimpse in to the development of colorectal cancer. The present study aimed to explore effect of CDH1 -160 polymorphism, CDH1 transcription and its protein E-cadherin expression on colorectal cancer, meanwhile uncovering the underlying mechanism. Specimens from cancer loci, adjacent cancer tissue, and distal normal tissue from colorectal cancer patients were collected for Hematoxylin-eosin staining to detect the histopathological change of colorectal mucosa. Direct sequencing and Quantitative Real-Time PCR were used to detect the CDH1 genotype and its mRNA expression, respectively. E-cadherin expression was detected using the ElivisionTM plus method. As a result, we found that the A allele of the CDH1 -160 may be a protective gene against colorectal cancer, and the C > A polymorphism may regulate its transcription activity and expression of E-cadherin. The decrease of the CDH1 mRNA transcription level and the absence of E-cadherin on the cytomembrane may promote intestinal mucosal carcinogenesis and accelerate cancer cell metastasis. Deficiency of cytomembrane expression of E-cadherin protein may have some early warning signs for malignant lesions of the gut mucosa.

Compaction of the preimplantation embryo is the earliest morphogenetic process essential for mammalian development, yet it remains unclear how round cells elongate to form a compacted embryo. Here, using live mouse embryo imaging, we demonstrate that cells extend long E-cadherin-dependent filopodia on to neighbouring cells, which control the cell shape changes necessary for compaction. We found that filopodia extension is tightly coordinated with cell elongation, whereas retraction occurs before cells become round again before dividing. Laser-based ablations revealed that filopodia are required to maintain elongated cell shapes. Moreover, molecular disruption of the filopodia components E-cadherin, α- and β-catenin, F-actin and myosin-X prevents cells from elongating and compacting the embryo. Finally, we show that early filopodia formation triggered by overexpressing myosin-X is sufficient to induce premature compaction. Our findings establish a role for filopodia during preimplantation embryonic development and provide an in vivo context to investigate the biological functions of filopodia in mammals. It has been unclear how round cells elongate during mouse embryo compaction. Plachta and colleagues use live imaging to demonstrate that E-cadherin-dependent filopodia extend to neighbouring cells to drive elongation and compaction.

Gastric cancer, a group of common malignancies, results in the most cancer mortality worldwide after only lung and colorectal cancer. Although familial gastric cancers have long been recognized, it was not until recently that they were discovered to be associated with mutations of specific genes. Mutations of , the gene encoding E-cadherin, are the most common germline mutations detected in gastric cancer and underlie hereditary diffuse gastric cancer (HDGC) syndrome. All reported HDGCs are the pure diffuse type by Lauren classification and are associated with dismal prognosis once the tumor invades the submucosa. Because germline mutations are inherited in an autosomal-dominant fashion and have high penetrance, the International Gastric Cancer Linkage Consortium (IGCLC) developed criteria to facilitate the screening of mutation carriers; these criteria have been proven to have excellent sensitivity and specificity. Recent histologic studies suggest that HDGC progresses through several stages. Even when the tumor becomes \"invasive\" in lamina propria, it may stay indolent for a long time. However, the molecular mechanisms that induce the transitions between stages and determine the length of the indolent phase remain to be determined. Although the standard management for mutation carriers is prophylactic total gastrectomy, many questions must be answered before the surgery can be done. These include the optimal surveillance strategy, the best strategy to choose surgical candidates, and the ideal time to perform surgery. In addition to increasing the risk of gastric cancer, germline mutations also increase the risk of invasive lobular carcinoma of the breast, and possibly colorectal adenocarcinoma, and are associated with blepharocheilodontic syndrome (a congenital development disorder). However, the optimal management of these conditions is less established owing to insufficient data regarding the risk of cancer development. This review focuses on molecular and histological findings in HDGC, as opposed to sporadic diffuse gastric cancer, and their implications for the management of mutation carriers and the diagnosis and treatment of HDGC. Other conditions associated with germline mutations and future research directions are also discussed.

The outer subventricular zone (OSVZ) is a germinal layer playing key roles in the development of the neocortex, with particular relevance in gyrencephalic species such as human and ferret, where it contains abundant basal radial glia cells (bRGCs) that promote cortical expansion. Here we identify a brief period in ferret embryonic development when apical RGCs generate a burst of bRGCs that become founders of the OSVZ. After this period, bRGCs in the OSVZ proliferate and self-renew exclusively locally, thereby forming a self-sustained lineage independent from the other germinal layers. The time window for the brief period of OSVZ bRGC production is delineated by the coincident downregulation of Cdh1 and Trnp1 , and their upregulation reduces bRGC production and prevents OSVZ seeding. This mechanism in cortical development may have key relevance in brain evolution and disease. The outer subventricular zone (OSVZ) contains basal radial glial cells (bRGC) involved in cortical expansion in gyrencephalic mammals. Here the authors identify a developmental time window with marked production of bRGCs required to found the OSVZ that is dependent on coincident downregulation of Cdh1 and Trnp1.

Abstract Chronic obstructive pulmonary disease (COPD) remains a major public health challenge that contributes greatly to mortality and morbidity worldwide. Although it has long been recognized that the epithelium is altered in COPD, there has been little focus on targeting it to modify the disease course. Therefore, mechanisms that disrupt epithelial cell function in patients with COPD are poorly understood. In this study, we sought to determine whether epigenetic reprogramming of the cell-cell adhesion molecule E-cadherin, encoded by the CDH1 gene, disrupts epithelial integrity. By reducing these epigenetic marks, we can restore epithelial integrity and rescue alveolar airspace destruction. We used differentiated normal and COPD-derived primary human airway epithelial cells, genetically manipulated mouse tracheal epithelial cells, and mouse and human precision-cut lung slices to assess the effects of epigenetic reprogramming. We show that the loss of CDH1 in COPD is due to increased DNA methylation site at the CDH1 enhancer D through the downregulation of the ten-eleven translocase methylcytosine dioxygenase (TET) enzyme TET1. Increased DNA methylation at the enhancer D region decreases the enrichment of RNA polymerase II binding. Remarkably, treatment of human precision-cut slices derived from patients with COPD with the DNA demethylation agent 5-aza-2′-deoxycytidine decreased cell damage and reduced air space enlargement in the diseased tissue. Here, we present a novel mechanism that targets epigenetic modifications to reverse the tissue remodeling in human COPD lungs and serves as a proof of concept for developing a disease-modifying target.

Signet ring cell adenocarcinomas (SRCCs) are a rare histological subtype of adenocarcinomas with a poor prognosis, typically due to advanced disease at diagnosis. A signet ring cell, mimicking its moniker, contains abundant intracytoplasmic mucin that pushes the nucleus to the periphery. In these cancers, this cell feature comprises more than 50% of the tumor. Despite predilection for the gastrointestinal tract, and in particular the stomach, primary SRCCs are also described in other sites, typically in case reports. This literature, however, lacks a standardized overview of the SRCC disease entity. Using a retrospective cohort approach, we summarize the clinicodemographic and mortality outcomes of SRCCs in thirteen primary sites, comprising 95% of all SRCCs in the Surveillance, Epidemiology, and End Results Program (SEER), a population-level cancer database covering nearly one-third of the United States population. SRCCs general trends compared to matching nonvariant adenocarcinomas are earlier age of onset, with initial presentation favoring higher rates of regional or distant disease presentation and poor tumor differentiation. After multivariable analysis, SRCCs typically have worse overall survivals, but substantial variances exist depending on tumor location. Identifying SRCCs at earlier disease stages is likely the single most important intervention to improving outcomes for these patients.