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Protein tyrosine kinase (PTK) activity has been implicated in pro-inflammatory gene expression following tumor necrosis factor-α (TNF-α) or interkeukin-1β (IL-1β) stimulation. However, the identity of responsible PTK(s) in cytokine signaling have not been elucidated. To evaluate which PTK is critical to promote the cytokine-induced inflammatory cell adhesion molecule (CAM) expression including VCAM-1, ICAM-1, and E-selectin in human aortic endothelial cells (HAoECs), we have tested pharmacological inhibitors of major PTKs: Src and the focal adhesion kinase (FAK) family kinases - FAK and proline-rich tyrosine kinase (Pyk2). We found that a dual inhibitor of FAK/Pyk2 (PF-271) most effectively reduced all three CAMs upon TNF-α or IL-1β stimulation compared to FAK or Src specific inhibitors (PF-228 or Dasatinib), which inhibited only VCAM-1 expression. In vitro inflammation assays showed PF-271 reduced monocyte attachment and transmigration on HAoECs. Furthermore, FAK/Pyk2 activity was not limited to CAM expression but was also required for expression of various pro-inflammatory molecules including MCP-1 and IP-10. Both TNF-α and IL-1β signaling requires FAK/Pyk2 activity to activate ERK and JNK MAPKs leading to inflammatory gene expression. Knockdown of either FAK or Pyk2 reduced TNF-α-stimulated ERK and JNK activation and CAM expression, suggesting that activation of ERK or JNK is specific through FAK and Pyk2. Finally, FAK/Pyk2 activity is required for VCAM-1 expression and macrophage recruitment to the vessel wall in a carotid ligation model in ApoE −/− mice. Our findings define critical roles of FAK/Pyk2 in mediating inflammatory cytokine signaling and implicate FAK/Pyk2 inhibitors as potential therapeutic agents to treat vascular inflammatory disease such as atherosclerosis.

Anaplastic thyroid cancer (ATC) is a rare but highly aggressive malignancy with a dismal prognosis. Although recent advances in targeted therapies have modestly improved survival, the molecular mechanisms driving ATC progression remain incompletely elucidated. Epithelial cell adhesion molecule (EpCAM), a multifunctional cell-surface protein, is implicated in proliferation, migration, and stemness in various cancers. However, its role in thyroid cancer progression remains unclear. In this study, we investigated the function of EpCAM in thyroid cancer cell lines of varying differentiation status. EpCAM expression was significantly elevated in ATC cell lines compared with differentiated thyroid cancer (DTC) lines. EpCAM knockdown by siRNA suppressed proliferation, adhesion, motility, and invasion in ATC cells, but had minimal effects on DTC cells. Morphological analyses revealed that EpCAM silencing induced differentiation features, including follicle-like structure formation and increased expression of thyroid differentiation markers such as thyroglobulin and PAX8 in ATC cells. Furthermore, EpCAM inhibition decreased mesenchymal marker expression, reduced filopodia formation, and suppressed extravasation of cancer cells into the lung in an in vivo mouse model. Mechanistically, EpCAM knockdown attenuated epithelial–mesenchymal transition (EMT)-related pathways but did not affect major proliferation signaling cascades in ATC cells. These findings suggest that EpCAM promotes dedifferentiation and metastatic potential in ATC through EMT modulation. Our results provide new insights into the role of EpCAM in thyroid cancer biology and highlight its potential as a therapeutic target in ATC. Further studies are warranted to elucidate the mechanisms linking EpCAM to anaplastic transformation and to explore the therapeutic efficacy of EpCAM-targeting strategies in aggressive thyroid cancers.

The aftermath of traumatization lives on in the neural and epigenetic traces creating a momentum of affliction in the psychological and social realm. Can psychotherapy reorganise these memories through changes in DNA methylation signatures? Using a randomised controlled parallel group design, we examined methylome-wide changes in saliva samples of 84 female former child soldiers from Eastern DR Congo before and six months after Narrative Exposure Therapy. Treatment predicted differentially methylated positions (DMPs) related to ALCAM , RIPOR2 , AFAP1 and MOCOS . In addition, treatment associations overlapped at gene level with baseline clinical and social outcomes. Treatment related DMPs are involved in memory formation—the key agent in trauma focused treatments—and enriched for molecular pathways commonly affected by trauma related disorders. Results were partially replicated in an independent sample of 53 female former child soldiers from Northern Uganda. Our results suggest a molecular impact of psychological treatment in women with war-related childhood trauma. Trial registration : Addressing Heightened Levels of Aggression in Traumatized Offenders With Psychotherapeutic Means (ClinicalTrials.gov Identifier: NCT02992561, 14/12/2016).

Synaptic cell adhesion molecules, including the neurexin ligands, neuroligins (NLs) and leucine-rich repeat transmembrane proteins (LRRTMs), are thought to organize synapse assembly and specify synapse function. To test the synaptic role of these molecules in vivo, we performed lentivirally mediated knockdown of NL3, LRRTM1, and LRRTM2 in CA1 pyramidal cells of WT and NL1 KO mice at postnatal day (P)0 (when synapses are forming) and P21 (when synapses are largely mature). P0 knockdown of NL3 in WT or NL1 KO neurons did not affect excitatory synaptic transmission, whereas P0 knockdown of LRRTM1 and LRRTM2 selectively reduced AMPA receptor-mediated synaptic currents. P0 triple knockdown of NL3 and both LRRTMs in NL1 KO mice yielded greater reductions in AMPA and NMDA receptor-mediated currents, suggesting functional redundancy between NLs and LRRTMs during early synapse development. In contrast, P21 knockdown of LRRTMs did not alter excitatory transmission, whereas NL manipulations supported a role for NL1 in maintaining NMDA receptor-mediated transmission. These results show that neurexin ligands in vivo form a dynamic synaptic cell adhesion network, with compensation between NLs and LRRTMs during early synapse development and functional divergence upon synapse maturation.

Nectin and nectin-like cell adhesion molecules (collectively referred as nectin family henceforth) are known to mediate cell-cell adhesion and related functions. While current literature suggests that nectins are prevalent in vertebrates, there are no in-depth analyses regarding the evolution of nectin family as a whole. In this work, we examine the evolutionary origin of the nectin family, using selected multicellular metazoans representing diverse clades whose whole genome sequencing data is available. Our results show that this family may have appeared earlier during metazoan evolution than previously believed. Systematic analyses indicate the order in which various members of nectin family seem to have evolved, with some nectin-like molecules appearing first, followed by the evolution of other members. Furthermore, we also found a few possible ancient homologues of nectins. While our study confirms the previous grouping of the nectin family into nectins and nectin-like molecules, it also shows poliovirus receptor (PVR/nectin-like-5) to possess characteristics that are intermediate between these two groups. Interestingly, except for PVR, the other nectins show surprising sequence conservations across species, suggesting evolutionary constraints due to critical roles played by these proteins.

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.

Background Gliomas account for the majority of primary human brain tumors and remain a challenging neoplasm for cure due to limited therapeutic options. Cell adhesion molecules play pivotal roles in the growth and progression of glial tumors. Roles of the adhesion molecules on glia (AMOG) and L1CAM (L1) in glioma cells have been shown to correlate with tumorigenesis: Increased expression of L1 and decreased expression of AMOG correlate with degree of malignancy. Methods We evaluated the interdependence in expression of these molecules by investigating the role of AMOG in vitro via modulation of L1 expression and analyzing apoptosis and cell senescence of glioma cells. Results Immunohistochemical staining of normal human cortical and glioma tissue microarrays demonstrated that AMOG expression was lower in human gliomas compared to normal tissue and is inversely correlated with the degree of malignancy. Moreover, reduction of AMOG expression in human glioblastoma cells elevated L1 expression, which is accompanied by decreased cell apoptosis as well as senescence. Conclusion AMOG and L1 interdependently regulate their expression levels not only in U-87 MG cells but also in U251 and SHG44 human glioma cell lines. The capacity of AMOG to reduce L1 expression suggests that methods for increasing AMOG expression may provide a therapeutic choice for the management of glial tumors with high expression of L1.

Many cell lines derived from solid cancers can form spheroids, which recapitulate tumor cell clusters and are more representative of the in vivo situation than 2D cultures. During spheroid formation, a small proportion of a variety of different colon cancer cell lines did not integrate into the sphere and lost cell-cell adhesion properties. An enrichment protocol was developed to augment the proportion of these cells to 100% purity. The basis for the separation of spheroids from non-spheroid forming (NSF) cells is simple gravity-sedimentation. This protocol gives rise to sub-populations of colon cancer cells with stable loss of cell-cell adhesion. SW620 cells lacked E-cadherin, DLD-1 cells lost α-catenin and HCT116 cells lacked P-cadherin in the NSF state. Knockdown of these molecules in the corresponding spheroid-forming cells demonstrated that loss of the respective proteins were indeed responsible for the NSF phenotypes. Loss of the spheroid forming phenotype was associated with increased migration and invasion properties in all cell lines tested. Hence, we identified critical molecules involved in spheroid formation in different cancer cell lines. We present here a simple, powerful and broadly applicable method to generate new sublines of tumor cell lines to study loss of cell-cell adhesion in cancer progression.

Drug-effect phenotypes in human lymphoblastoid cell lines recently allowed to identify CHL1 (cell adhesion molecule with homology to L1CAM), GAP43 (growth-associated protein 43) and ITGB3 (integrin beta 3) as new candidates for involvement in the antidepressant effect. CHL1 and ITGB3 code for adhesion molecules, while GAP43 codes for a neuron-specific cytosolic protein expressed in neuronal growth cones; all the three gene products are involved in synaptic plasticity. Sixteen polymorphisms in these genes were genotyped in two samples ( n =369 and 90) with diagnosis of major depressive episode who were treated with antidepressants in a naturalistic setting. Phenotypes were response, remission and treatment-resistant depression. Logistic regression including appropriate covariates was performed. Genes associated with outcomes were investigated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) genome-wide study ( n =1861) as both individual genes and through a pathway analysis (Reactome and String databases). Gene-based analysis suggested CHL1 rs4003413, GAP43 rs283393 and rs9860828, ITGB3 rs3809865 as the top candidates due to their replication across the largest original sample and the STAR*D cohort. GAP43 molecular pathway was associated with both response and remission in the STAR*D, with ELAVL4 representing the gene with the highest percentage of single nucleotide polymorphisms (SNPs) associated with outcomes. Other promising genes emerging from the pathway analysis were ITGB1 and NRP1 . The present study was the first to analyze cell adhesion genes and their molecular pathways in antidepressant response. Genes and biomarkers involved in neuronal adhesion should be considered by further studies aimed to identify predictors of antidepressant response.

The evolutionary transition from diffusion-mediated cell-cell communication to faster, targeted synaptic signaling in animal nervous systems is still unclear. Genome sequencing analyses have revealed a widespread distribution of synapse-related genes among early-diverging metazoans, but how synaptic machinery evolved remains largely unknown. Here, we examine the function of neurexins (Nrxns), a family of presynaptic cell adhesion molecules with critical roles in bilaterian chemical synapses, using the cnidarian model, Nematostella vectensis . Delta-Nrxns are expressed mainly in neuronal cell clusters that exhibit both peptidergic and classical neurotransmitter signaling. Knockdown of δ-Nrxn reduces spontaneous peristalsis of N. vectensis polyps. Interestingly, gene knockdown and pharmacological studies suggest that δ-Nrxn is involved in glutamate- and glycine-mediated signaling rather than peptidergic signaling. Knockdown of the epithelial α-Nrxn reveals a major role in cell adhesion between ectodermal and endodermal epithelia. Overall, this study provides molecular, functional, and cellular insights into the pre-neural function of Nrxns, as well as key information for understanding how and why they were recruited to the synaptic machinery. The evolutionary origin of neural synapses is unclear. Analysis of cnidarian neurexins provides clues as to when this synaptic hub molecule, which had an ancestral role in adhesion between heterotypic epithelial cells, acquired a neuronal function.