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Variants in EPHB4 (Ephrin type B receptor 4), a transmembrane tyrosine kinase receptor, have been identified in individuals with various vascular anomalies including Capillary Malformation‐Arteriovenous Malformation syndrome 2 and lymphatic‐related (non‐immune) fetal hydrops (LRHF). Here, we identify two novel variants in EPHB4 that disrupt the SAM domain in two unrelated individuals. Proband 1 presented within the LRHF phenotypic spectrum with hydrops, and proband 2 presented with large nuchal translucency prenatally that spontaneously resolved in addition to dysmorphic features on exam postnatally. These are the first disease associated variants identified that do not disrupt EPHB4 protein expression or tyrosine‐kinase activity. We identify that EPHB4 SAM domain disruptions can lead to aberrant downstream signaling, with a loss of the SAM domain resulting in elevated MAPK signaling in proband 1, and a missense variant within the SAM domain resulting in increased cell proliferation in proband 2. This data highlights that a functional SAM domain is required for proper EPHB4 function and vascular development. [ABSTRACT FROM AUTHOR]

Pediatric neoplasms represent a complex group of malignancies that pose unique challenges in terms of diagnosis, treatment, and understanding of the underlying molecular pathogenetic mechanisms. Erythropoietin-producing hepatocellular receptors (EPHs), the largest family of receptor tyrosine kinases and their membrane-tethered ligands, ephrins, orchestrate short-distance cell–cell signaling and are intricately involved in cell-pattern morphogenesis and various developmental processes. Unraveling the role of the EPH/ephrin signaling pathway in the pathophysiology of pediatric neoplasms and its clinical implications can contribute to deciphering the intricate landscape of these malignancies. The bidirectional nature of the EPH/ephrin axis is underscored by emerging evidence revealing its capacity to drive tumorigenesis, fostering cell–cell communication within the tumor microenvironment. In the context of carcinogenesis, the EPH/ephrin signaling pathway prompts a reevaluation of treatment strategies, particularly in pediatric oncology, where the modest progress in survival rates and enduring treatment toxicity necessitate novel approaches. Molecularly targeted agents have emerged as promising alternatives, prompting a shift in focus. Through a nuanced understanding of the pathway's intricacies, we aim to lay the groundwork for personalized diagnostic and therapeutic strategies, ultimately contributing to improved outcomes for young patients grappling with neoplastic challenges. [ABSTRACT FROM AUTHOR]

Studies trying to understand cell death, this ultimate biological process, can be traced back to a century ago. Yet, unlike many other fashionable research interests, research on cell death is more alive than ever. New modes of cell death are discovered in specific contexts, as are new molecular pathways. But what is "cell death", really? This question has not found a definitive answer yet. Nevertheless, part of the answer is irreversibility, whereby cells can no longer recover from stress or injury. Here, we identify the most distinctive features of different modes of cell death, focusing on the executive final stages. In addition to the final stages, these modes can differ in their triggering stimulus, thus referring to the initial stages. Within this framework, we use a few illustrative examples to examine how intercellular communication factors in the demise of cells. First, we discuss the interplay between cell–cell communication and cell death during a few steps in the early development of multicellular organisms. Next, we will discuss this interplay in a fully developed and functional tissue, the gut, which is among the most rapidly renewing tissues in the body and, therefore, makes extensive use of cell death. Furthermore, we will discuss how the balance between cell death and communication is modified during a pathological condition, i.e., colon tumorigenesis, and how it could shed light on resistance to cancer therapy. Finally, we briefly review data on the role of cell–cell communication modes in the propagation of cell death signals and how this has been considered as a potential therapeutic approach. Far from vainly trying to provide a comprehensive review, we launch an invitation to ponder over the significance of cell death diversity and how it provides multiple opportunities for the contribution of various modes of intercellular communication. [ABSTRACT FROM AUTHOR]

Background: Erythropoietin-producing hepatocellular (EPH) receptors are the largest known family of receptor tyrosine kinases characterized in humans. These proteins are involved in tissue organization, synaptic plasticity, vascular development and the progression of various diseases including cancer. The Erythropoietin-producing hepatocellular receptor tyrosine kinase member EphB6 is a pseudokinase which has not attracted an equivalent amount of interest as its enzymatically-active counterparts. The aim of this study was to assess the expression of EphB6 in pituitary tumors. Methods and Results: Human normal pituitaries and pituitary tumors were examined for EphB6 mRNA expression using real-time PCR and for EphB6 protein by immunohistochemistry and Western blotting. EphB6 was highly expressed in non-functioning pituitary neuroendocrine tumors (NF-PitNETs) versus the normal pituitary and GH-secreting PitNETs. EphB6 mRNA expression was correlated with tumor size. Conclusions: Our results suggest EphB6 aberrant expression in NF-PitNETs. Future studies are warranted to determine the role and significance of EphB6 in NF-PitNETs tumorigenesis. [ABSTRACT FROM AUTHOR]

Background: The polymeric immunoglobulin receptor (pIgR) is a transmembrane transporter of polymeric IgA through the intestinal epithelium. Its overexpression has been reported in several cancers, but its role as a diagnostic and prognostic biomarker of oncogenesis is currently unclear. Method: A literature search was conducted to summarize the functions of pIgR, its expression levels, and its clinical implications. Results: pIgR expression has previously been investigated by proteomic analysis, RNA sequencing, and tissue microarray at the level of both RNA and protein in various cancers including pancreatic, esophageal, gastric, lung, and liver. However, studies have reported inconsistent results on how pIgR levels affect clinical outcomes such as survival rate and chemotherapy resistance. Possible explanations include pIgR mRNA levels being minimally correlated with the rate of downstream pIgR protein synthesis, and the diversity of antibodies used in immunohistochemistry studies further magnifying this ambiguity. In ovarian cancer cells, the transcytosis of IgA accompanied a series of transcriptional changes in intracellular inflammatory pathways that inhibit the progression of cancer, including the upregulation of IFN-gamma and downregulation of tumor-promoting ephrins. These findings suggest that both the levels of pIgR and secreted IgA from tumor-infiltrating B cells affect clinical outcomes. Conclusion: Overall, no direct correlation was observed between the levels of pIgR inside tumor tissue and the clinical features in cancer patients. Measuring pIgR protein levels with a more specific and possibly chemically defined antibody, along with tumoral IgA, is a potential solution to better understand the pathways and consequences of pIgR overexpression in cancer cells. [ABSTRACT FROM AUTHOR]

Neurulation transforms the neuroectoderm into the neural tube. This transformation relies on reorganising the configurational relationships between the orientations of intrinsic polarities of neighbouring cells. These orientational intercellular relationships are established, maintained, and modulated by orientational cell adhesions (OCAs). Here, using zebrafish (Danio rerio) neurulation as a major model, we propose a new perspective on how OCAs contribute to the parallel, antiparallel, and opposing intercellular relationships that underlie the neural plate–keel–rod–tube transformation, a stepwise process of cell aggregation followed by cord hollowing. We also discuss how OCAs in neurulation may be regulated by various adhesion molecules, including cadherins, Eph/Ephrins, Claudins, Occludins, Crumbs, Na+/K+‐ATPase, and integrins. By comparing neurulation among species, we reveal that antiparallel OCAs represent a conserved mechanism for the fusion of the neural tube. Throughout, we highlight some outstanding questions regarding OCAs in neurulation. Answers to these questions will help us understand better the mechanisms of tubulogenesis of many tissues. [ABSTRACT FROM AUTHOR]

The Eph kinases are the largest receptor tyrosine kinases (RTKs) family in humans. PC3 human prostate adenocarcinoma cells are a well-established model for studying Eph–ephrin pharmacology as they naturally express a high level of EphA2, a promising target for new cancer therapies. A pharmacological approach with agonists did not show significant efficacy on tumor growth in prostate orthotopic murine models, but reduced distal metastasis formation. In order to improve the comprehension of the pharmacological targeting of Eph receptors in prostate cancer, in the present work, we investigated the efficacy of Eph antagonism both in vitro and in vivo, using UniPR1331, a small orally bioavailable Eph–ephrin interaction inhibitor. UniPR1331 was able to inhibit PC3 cells' growth in vitro in a dose-dependent manner, affecting the cell cycle and inducing apoptosis. Moreover, UniPR1331 promoted the PC3 epithelial phenotype, downregulating epithelial mesenchymal transition (EMT) markers. As a consequence, UniPR1331 reduced in vitro PC3 migration, invasion, and vasculomimicry capabilities. The antitumor activity of UniPR1331 was confirmed in vivo when administered alone or in combination with cytotoxic drugs in PC3-xenograft mice. Our results demonstrated that Eph antagonism is a promising strategy for inhibiting prostate cancer growth, especially in combination with cytotoxic drugs. [ABSTRACT FROM AUTHOR]

During infection the host relies on pattern-recognition receptors to sense invading fungal pathogens to launch immune defense mechanisms. While fungal recognition and immune effector responses are organ and cell type specific, during disseminated candidiasis myeloid cells exacerbate collateral tissue damage. The β-glucan receptor ephrin type-A 2 receptor (EphA2) is required to initiate mucosal inflammatory responses during oral Candida infection. Here we report that EphA2 promotes renal immunopathology during disseminated candidiasis. EphA2 deficiency leads to reduced renal inflammation and injury. Comprehensive analyses reveal that EphA2 restrains IL-23 secretion from and migration of dendritic cells. IL-23 signaling prevents ferroptotic host cell death during infection to limit inflammation and immunopathology. Further, host cell ferroptosis limits antifungal effector functions via releasing the lipid peroxidation product 4-hydroxynonenal to induce various forms of cell death. Thus, we identify ferroptotic cell death as a critical pathway of Candida-mediated renal immunopathology that opens a new avenue to tackle Candida infection and inflammation.

Hepatic fibrosis is the common pathological change that occurs due to increased synthesis and accumulation of extracellular matrix components. Chronic insult from hepatotoxicants leads to liver cirrhosis, which if not reversed timely using appropriate therapeutics, liver transplantation remains the only effective therapy. Often the disease further progresses into hepatic carcinoma. Although there is an increased advancement in understanding the pathological phenotypes of the disease, additional knowledge of the novel molecular signaling mechanisms involved in the disease progression would enable the development of efficacious therapeutics. Ephrin–Eph molecules belong to the largest family of receptor tyrosine kinases (RTKs) which are identified to play a crucial role in cellular migratory functions, during morphological and developmental stages. Additionally, they contribute to the growth of a multicellular organism as well as in pathological conditions like cancer, and diabetes. A wide spectrum of mechanistic studies has been performed on ephrin–Eph RTKs in various hepatic tissues under both normal and diseased conditions revealing their diverse roles in hepatic pathology. This systematic review summarizes the liver-specific ephrin–Eph RTK signaling mechanisms and recognizes them as druggable targets for mitigating hepatic pathology. [ABSTRACT FROM AUTHOR]

Simple Summary: The EPH/ephrin signaling axis holds a pivotal role in a plethora of physiologic processes during embryonic development and adult life, while more recent studies highlight its implication in the pathogenesis of multiple types of solid tumors. Different patterns of EPH/ephrin expression have been identified in normal hematopoiesis concerning the maintenance, differentiation, and function of hematopoietic stem cells and their mature offspring. Emerging data suggest that EPH/ephrin aberrations contribute to the pathogenesis of various hematologic malignancies, exerting both tumor-promoting and tumor-suppressive functions. Thus, unraveling the intricate role of EPH/ephrin signaling in the setting of hematologic neoplasia can contribute to the development of promising therapeutic targets to overcome unmet needs. Erythropoietin-producing hepatocellular carcinoma receptors (EPHs) represent the largest family of receptor tyrosine kinases (RTKs). EPH interaction with ephrins, their membrane-bound ligands, holds a pivotal role in embryonic development, while, though less active, it is also implicated in various physiological functions during adult life. In normal hematopoiesis, different patterns of EPH/ephrin expression have been correlated with hematopoietic stem cell (HSC) maintenance and lineage-committed hematopoietic progenitor cell (HPC) differentiation, as well as with the functional properties of their mature offspring. Research in the field of hematologic malignancies has unveiled a rather complex involvement of the EPH/ephrinsignaling pathway in the pathophysiology of these neoplasms. Aberrations in genetic, epigenetic, and protein levels have been identified as possible players implicated both in tumor progression and suppression, while correlations have also been highlighted regarding prognosis and response to treatment. Initial efforts to therapeutically target the EPH/ephrin axis have been undertaken in the setting of hematologic neoplasia but are mainly confined to the preclinical level. To this end, deciphering the complexity of this signaling pathway both in normal and malignant hematopoiesis is necessary. [ABSTRACT FROM AUTHOR]

EPH/EPHRIN signaling is essential to many aspects of tissue self-organization and morphogenesis, but little is known about how EPH/EPHRIN signaling regulates cell mechanics during these processes. Here, we use a series of approaches to examine how EPH/EPHRIN signaling drives cellular self-organization. Contact angle measurements reveal that EPH/EPHRIN signaling decreases the stability of heterotypic cell:cell contacts through increased cortical actomyosin contractility. We find that EPH/EPHRIN-driven cell segregation depends on actomyosin contractility but occurs independently of directed cell migration and without changes in cell adhesion. Atomic force microscopy and live cell imaging of myosin localization support that EPH/EPHRIN signaling results in increased cortical tension. Interestingly, actomyosin contractility also nonautonomously drives increased EPHB2:EPHB2 homotypic contacts. Finally, we demonstrate that changes in tissue organization are driven by minimization of heterotypic contacts through actomyosin contractility in cell aggregates and by mouse genetics experiments. These data elucidate the biomechanical mechanisms driving EPH/EPHRIN-based cell segregation wherein differences in interfacial tension, regulated by actomyosin contractility, govern cellular self-organization.

Pediatric neoplasms represent a complex group of malignancies that pose unique challenges in terms of diagnosis, treatment, and understanding of the underlying molecular pathogenetic mechanisms. Erythropoietin-producing hepatocellular receptors (EPHs), the largest family of receptor tyrosine kinases and their membrane-tethered ligands, ephrins, orchestrate short-distance cell–cell signaling and are intricately involved in cell-pattern morphogenesis and various developmental processes. Unraveling the role of the EPH/ephrin signaling pathway in the pathophysiology of pediatric neoplasms and its clinical implications can contribute to deciphering the intricate landscape of these malignancies. The bidirectional nature of the EPH/ephrin axis is underscored by emerging evidence revealing its capacity to drive tumorigenesis, fostering cell–cell communication within the tumor microenvironment. In the context of carcinogenesis, the EPH/ephrin signaling pathway prompts a reevaluation of treatment strategies, particularly in pediatric oncology, where the modest progress in survival rates and enduring treatment toxicity necessitate novel approaches. Molecularly targeted agents have emerged as promising alternatives, prompting a shift in focus. Through a nuanced understanding of the pathway’s intricacies, we aim to lay the groundwork for personalized diagnostic and therapeutic strategies, ultimately contributing to improved outcomes for young patients grappling with neoplastic challenges.

The article presents several science news. Topics discusses include doubling atmospheric carbon-dioxide concentration increases the impact on global surface air temperature by about 25 percent; and the CRISPR-Cas systems serving as efficient barriers against viral infections and the discovery of a cAn-dependent effector named Cami1 that blocks bacterial protein synthesis in response to type III CRISPR-Cas signaling.

Inorganic arsenic oxides have been identified as carcinogens in several human tissues, including epidermis. Due to the chemical similarity between trivalent inorganic arsenic (arsenite) and antimony (antimonite), we hypothesized that common intracellular targets lead to similarities in cellular responses. Indeed, transcriptional and proteomic profiling revealed remarkable similarities in differentially expressed genes and proteins resulting from exposure of cultured human epidermal keratinocytes to arsenite and antimonite in contrast to comparisons of arsenite with other metal compounds. These data were analyzed to predict upstream regulators and affected signaling pathways following arsenite and antimonite treatments. A majority of the top findings in each category were identical after treatment with either compound. Inspection of the predicted upstream regulators led to previously unsuspected roles for oncostatin M, corticosteroids and ephrins in mediating cellular response. The influence of these predicted mediators was then experimentally verified. Together with predictions of transcription factor effects more generally, the analysis has led to model signaling networks largely accounting for arsenite and antimonite action. The striking parallels between responses to arsenite and antimonite indicate the skin carcinogenic risk of exposure to antimonite merits close scrutiny.

The ephrin-B family of membrane-bound ligands is involved in skeletal patterning, osteogenesis, and bone homeostasis. Yet, despite the increasing collection of data affirming their importance in bone, the Eph tyrosine kinases that serve as the receptors for these ephrins in osteoblast stem cell niches remain unidentified. Here we report the expression of EphB3 at sites of bone growth in the embryo, especially at the calvaria suture fronts, periosteum, chondrocytes, and trabeculae of developing long bones. Strong EphB3 expression persisted in the adult calvarial sutures and in the proliferative chondrocytes of long bones, both of which are documented niches for osteoblastic stem cells. We observed EphB3-positive cells in the tissue filling a created calvarial injury, further implying EphB3 involvement in bone healing. Genetic knockout of EphB3 caused an increase in the bone tissue volume as a fraction of total volume in 6-week-old calvaria and in femoral trabecular density, compared to wild type controls. This difference resolved by 12 weeks of age, when we instead observed an increase in the bone volume of femoral trabeculae and in trabecular thickness. Our data identify EphB3 as a candidate regulator of osteogenesis either alone or in combination with other bone-expressed Ephs, and indicate that it appears to function as a limiter of bone growth. [ABSTRACT FROM AUTHOR]

Ephrin receptors constitute a large family of receptor tyrosine kinases in mammals that through interaction with cell surface-anchored ephrin ligands regulate multiple different cellular responses in numerous cell types and tissues. In the cardiovascular system, studies performed in vitro and in vivo have pointed to a critical role for Ephrin receptor B4 (EPHB4) as a regulator of blood and lymphatic vascular development and function. However, in this role, EPHB4 appears to act not as a classical growth factor receptor but instead functions to dampen the activation of the Ras-mitogen activated protein signaling (MAPK) pathway induced by other growth factor receptors in endothelial cells (EC). To inhibit the Ras-MAPK pathway, EPHB4 interacts functionally with Ras p21 protein activator 1 (RASA1) also known as p120 Ras GTPase-activating protein. Here, we review the evidence for an inhibitory role for an EPHB4–RASA1 interface in EC. We further discuss the mechanisms by which loss of EPHB4–RASA1 signaling in EC leads to blood and lymphatic vascular abnormalities in mice and the implications of these findings for an understanding of the pathogenesis of vascular anomalies in humans caused by mutations in EPHB4 and RASA1 genes. Last, we provide insights into possible means of drug therapy for EPHB4- and RASA1-related vascular anomalies. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is a major concern for health care systems worldwide, since its mortality remains unaltered despite the surge in cutting-edge science. The EPH/ephrin signaling system was first investigated in the 1980s. EPH/ephrins have been shown to exert bidirectional signaling and cell-to-cell communication, influencing cellular morphology, adhesion, migration and invasion. Recent studies have highlighted the critical role of the EPH/ephrin system in various physiologic processes, including cellular proliferation, survival, synaptic plasticity and angiogenesis. Thus, it has become evident that the EPH/ephrin signaling system may have compelling effects on cell homeostasis that contribute to carcinogenesis. In particular, the EPH/ephrins have an impact on pancreatic morphogenesis and development, whereas several EPHs and ephrins are altered in PDAC. Several clinical and preclinical studies have attempted to elucidate the effects of the EPH/ephrin pathway, with multilayered effects on PDAC development. These studies have highlighted its highly promising role in the diagnosis, prognosis and therapeutic management of PDAC. The aim of this review is to explore the obscure aspects of the EPH/ephrin system concerning the development, physiology and homeostasis of the pancreas. [ABSTRACT FROM AUTHOR]

Eph receptor tyrosine kinases play critical functions during development, in the formation of tissue and organ borders, and the vascular and neural systems. Uniquely among tyrosine kinases, their activities are controlled by binding to membrane-bound ligands, called ephrins. Ephs and ephrins generally have a low expression in adults, functioning mainly in tissue homeostasis and plasticity, but are often overexpressed in cancers, where they are especially associated with undifferentiated or progenitor cells, and with tumour development, vasculature, and invasion. Mutations in Eph receptors also occur in various tumour types and are suspected to promote tumourigenesis. Ephs and ephrins have the capacity to operate as both tumour promoters and tumour suppressors, depending on the circumstances. They have been demonstrated to impact tumour cell proliferation, migration, and invasion in vitro, as well as tumour development, angiogenesis, and metastases in vivo, making them potential therapeutic targets. However, successful development of therapies will require detailed understanding of the opposing roles of Ephs in various cancers. In this review, we discuss the variations in Eph expression and functions in a variety of malignancies. We also describe the multiple strategies that are currently available to target them in tumours, including preclinical and clinical development. [ABSTRACT FROM AUTHOR]

• Seminal discoveries of Friedrich Bonhoeffer and colleagues are highlighted. • Similarities and differences between the regulation of Robo and EphR-mediated repulsion are discussed. • New areas for future research are highlighted. Friedrich Bonhoeffer made seminal contributions to the study of axon guidance in the developing nervous system. His discoveries of key cellular and molecular mechanisms that dictate wiring specificity laid the foundation for countless investigators who have followed in his footsteps. Perhaps his most significant contribution was the cloning and characterization of members of the conserved ephrin family of repulsive axon guidance cues. In this review, we highlight the major contributions that Bonhoeffer and his colleagues made to the field of axon guidance, and discuss ongoing investigations into the diverse array of mechanisms that ensure that axon repulsion is precisely regulated to allow for accurate pathfinding. Specifically, we focus our discussion on the post-translational regulation of two major families of repulsive axon guidance factors: ephrin ligands and their Eph receptors, and slit ligands and their Roundabout (Robo) receptors. We will give special emphasis to the ways in which regulated endocytic trafficking events allow navigating axons to adjust their responses to repellant signals and how these trafficking events are intimately related to receptor signaling. By highlighting parallels and differences between the regulation of these two important repulsive axon guidance pathways, we hope to identify key outstanding questions for future investigation. [ABSTRACT FROM AUTHOR]

Lung cancer (LC) is the leading cause of cancer death in the United States. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest receptor tyrosine kinases (RTKs) family in mammals. EPHs along with their ligands, EPH-family receptor-interacting proteins (ephrins), have been found to be either up- or downregulated in LC cells, hence exhibiting a defining role in LC carcinogenesis and tumor progression. In their capacity as membrane-bound molecules, EPHs/ephrins may represent feasible targets in the context of precision cancer treatment. In order to investigate available therapeutics targeting the EPH/ephrin system in LC, a literature review was conducted, using the MEDLINE, LIVIVO, and Google Scholar databases. EPHA2 is the most well-studied EPH/ephrin target in LC treatment. The targeting of EPHA2, EPHA3, EPHA5, EPHA7, EPHB4, EPHB6, ephrin-A1, ephrin-A2, ephrin-B2, and ephrin-B3 in LC cells or xenograft models not only directly correlates with a profound LC suppression but also enriches the effects of well-established therapeutic regimens. However, the sole clinical trial incorporating a NSCLC patient could not describe objective anti-cancer effects after anti-EPHA2 antibody administration. Collectively, EPHs/ephrins seem to represent promising treatment targets in LC. However, large clinical trials still need to be performed, with a view to examining the effects of EPH/ephrin targeting in the clinical setting. [ABSTRACT FROM AUTHOR]

Acoustic communication relies crucially on accurate interpretation of information about the intensity, frequency, timing, and location of diverse sound stimuli in the environment. To meet this demand, neurons along different levels of the auditory system form precisely organized neural circuits. The assembly of these precise circuits requires tight regulation and coordination of multiple developmental processes. Several groups of axon guidance molecules have proven critical in controlling these processes. Among them, the family of Eph receptors and their ephrin ligands emerge as one group of key players. They mediate diverse functions at multiple levels of the auditory pathway, including axon guidance and targeting, topographic map formation, as well as cell migration and tissue pattern formation. Here, we review our current knowledge of how Eph and ephrin molecules regulate different processes in the development and maturation of central auditory circuits. Key Findings: Eph/ephrin signaling regulates the segregation and patterning of eighth cranial nerve central projections and tonotopic map precision of the CN.Eph/ephrin signaling regulates the assembly of the sound localization circuit in the auditory brainstem.Eph/ephrin signaling regulates the formation of tonotopic projections in the inferior colliculus.Eph/ephrin signaling regulates frequency tuning and axon targeting in the medial geniculate body and auditory cortex. [ABSTRACT FROM AUTHOR]

In vertebrates, the Eph/ephrin family of signaling molecules is a large group of membrane-bound proteins that signal through a myriad of mechanisms and effectors to play diverse roles in almost every tissue and organ system. Though Eph/ephrin signaling has functions in diverse biological processes, one core developmental function is in the regulation of cell position and tissue morphology by regulating cell migration and guidance, cell segregation, and boundary formation. Often, the role of Eph/ephrin signaling is to translate patterning information into physical movement of cells and changes in morphology that define tissue and organ systems. In this review, we focus on recent advances in the regulation of these processes, and our evolving understanding of the in vivo signaling mechanisms utilized in distinct developmental contexts.

A commentary published in the Proceedings of the National Academy of Sciences discusses the use of DNA-encoded drug discovery to advance therapies for endometriosis and cancer. The study identifies novel pan-EPH kinase inhibitors that could potentially lead to nonhormonal treatments for these diseases. The researchers used a high-throughput screening method called DEC-Tec, which leverages DNA-encoded chemical libraries to rapidly identify bioactive molecules. The study's findings have the potential to improve the quality of life for individuals affected by these conditions and open new avenues for research in the future. [Extracted from the article]

Blocking the EphB4-EphrinB2 pathway has efficacy in preclinical models of prostate cancer. We conducted a single arm trial using sEphB4-HSA in patients with advanced prostate cancer using a Simon 2-stage design. Fourteen patients enrolled in the study. No patient had a confirmed response, and the study was stopped for futility. sEphB4-HSA monotherapy had no anti-tumor activity in patients with mCRPC. Introduction: Ephrin receptors and their membrane-localized ligands induce bidirectional signaling and facilitate tumorstroma interactions. Blocking the EphB4-EphrinB2 pathway, which can be accomplished by soluble EphB4 conjugated to human serum albumin (sEphB4-HSA), promotes cell death in preclinical models of aggressive prostate cancer. We hypothesized that targeting the EphB4-EphrinB2 pathway may serve as a therapeutic target in the treatment of metastatic castration resistant prostate cancer (mCRPC). Patients and Methods: We conducted a single arm, phase II trial in patients with progressive mCRPC who had received no more than 3 prior therapies for mCRPC. sEphB4- HSA 1000 mg IV was administered every 2 weeks, extending to 3 weeks starting from cycle 7. The primary endpoint was confirmed prostate specific antigen (PSA) response rate. We employed a Simon 2-stage Minimax design with 15 patients in the first stage and 10 additional patients in the second stage. Results: Fourteen eligible patients enrolled in the study with median age of 73.5 years (range: 52-83) and median baseline PSA of 65.11 ng/mL (range: 7.77-2850 ng/mL). Most patients received 3 prior therapies for mCRPC. The median treatment duration with sEphB4-HSA was 6.5 weeks (range: 2-35 weeks). Three patients exper ienced a ser ious adverse event potentially related to therapy, including 1 patient with a grade 5 event (cerebral vascular accident) possibly related to the study drug. No patient had a confirmed PSA response, and the study was stopped for futility. Thirteen patients had PSA progression. The median time to PSA progression was 28 days (90% CI: 28-42 days), and median time to radiologic progression was 55 days (90% CI: 54-72 days). Of 3 patients with measurable disease, 2 had stable disease and one had progressive disease. Conclusion: In patients with mCRPC who progressed on prior second generation AR-targeted therapy, sEphB4-HSA monotherapy had no discernable anti-tumor activity. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common malignant tumor in women. Erythropoietin-producing hepatocellular receptors (EPHs), receptor tyrosine kinases binding the membrane-bound proteins ephrins, are differentially expressed in BC, and correlate with carcinogenesis and tumor progression. With a view to examining available therapeutics targeting the EPH/ephrin system in BC, a literature review was conducted, using the MEDLINE, LIVIVO, and Google Scholar databases. EPHA2 is the most studied EPH/ephrin target in BC treatment. The targeting of EPHA2, EPHA10, EPHB4, ephrin-A2, ephrin-A4, as well as ephrin-B2 in BC cells or xenograft models is associated with apoptosis induction, tumor regression, anticancer immune response activation, and impaired cell motility. In conclusion, EPHs/ephrins seem to represent promising future treatment targets in BC. [ABSTRACT FROM AUTHOR]

Kupffer cells are maintained via self-renewal in specific microenvironmental niches, primarily the liver sinusoidal endothelial cells (LSECs). In this study, we propagated tissue-resident macrophages (Mø) from mouse liver using mixed culture with hepatic fibroblastic cells. Propagated liver Mø express Id3, Lxra and Spic transcription factors, which are required for Kupffer cell characterization. Thus, Kupffer cell properties are likely to be maintained in liver Mø propagated using mixed culture with fibroblastic cells. We revealed (i) gene expression of certain Eph receptors and ephrin ligands including EphA2, ephrin-A1, EphB4, and ephrin-B1 in propagated liver Mø and primary LSECs, (ii) immunohistochemical localization of these Eph/ephrin member molecules indicating common expression in Kupffer cells and LSECs, and (iii) surface expression of several integrin α and β subunits, including α4β1, αLβ2, αMβ2, and αXβ2 integrin in propagated liver Mø and that of the corresponding ligands ICAM-1 and VCAM-1 in primary LSECs. Moreover, EphA/ephrin-A and EphB/ephrin-B interactions promoted liver Mø adhesion to the ICAM-1-adsorbed surface, which mimicked that of LSECs and may be implicated in the residence of Kupffer cells in the liver sinusoid. Further studies on regulating the residence and regeneration of Kupffer cells in related hepatic disorders are required to validate our findings. [ABSTRACT FROM AUTHOR]

Eph‐ephrin signaling acts as spatial cue to define the tissue boundaries, the axonal growth, or the organization of compartmentalized tissues in vertebrates. By the regulation of tension, adhesion, and repulsion, intermingling of cells expressing the membrane‐tethered ligand and cells expressing the membrane‐tethered receptor is prevented. Despite being surface‐bound, most of the studies addressing Eph‐ephrin interactions use soluble ligands, which lack the spatial component needed to study tissue patterning. Here, it is shown that spatial patterns of ephrin ligands can modulate the organization of the different compartments in organoid‐derived intestinal epithelial monolayers. A modified version of the microcontact printing technique is used to create spatial cues of ephrin ligand on basement membrane surrogates. It is shown that both ligand concentration and cellular density can impact the strength of the repulsive effect triggered by Eph‐ephrin signaling. Finally, it is demonstrated that by using micropatterned ephrin spatial cues one can modify the orientation of intestinal crypts and align them in the direction set by the pattern. The approach presented here is believed to be an excellent tool to study exogenous signal with relevant spatial distribution in vivo. [ABSTRACT FROM AUTHOR]

Erythropoietin‐producing hepatoma (Eph) receptors belong to a family of tyrosine kinase receptors that plays a pivotal role in the development of the brain. Eph can be divided broadly into two groups, namely, EphA and EphB, comprising nine and five members, respectively. In recent years, the role of EphA‐4 has become increasingly apparent in the onset of Alzheimer's disease (AD). Emerging evidence suggests that EphA‐4 results in synaptic dysfunction, which in turn promotes the progression of AD. Moreover, pharmacological or genetic ablation of EphA‐4 in the murine model of AD can alleviate the symptoms. The current review summarizes different pathways by which EphA‐4 can influence pathogenesis. Since, majority of the studies had reported the protective effect of EphA‐4 inhibition during AD, designing therapeutics based on decreasing its enzymatic activity might be necessary for introducing the novel interventions. Therefore, the review described peptide and nanobodies inhibitors of EphA‐4 that exhibit the potential to modulate EphA‐4 and could be used as lead molecules for the targeted therapy of AD. [ABSTRACT FROM AUTHOR]

The article presents a study on Cytomegalovirus (CMV) reactivation and its affect on associated disease. It explores a signaling pathway that plays a central role in the balance between CMV latency and reactivation and identifies a common therapeutic cancer treatment that elevates the risk of CMV-associated disease.

The eye lens is a transparent, ellipsoid organ in the anterior chamber of the eye that is required for fine focusing of light onto the retina to transmit a clear image. Cataracts, defined as any opacity in the lens, remains the leading cause of blindness in the world. Recent studies in humans and mice indicate that Eph–ephrin bidirectional signaling is important for maintaining lens transparency. Specifically, mutations and polymorphisms in the EphA2 receptor and the ephrin-A5 ligand have been linked to congenital and age-related cataracts. It is unclear what other variants of Ephs and ephrins are expressed in the lens or whether there is preferential expression in epithelial vs. fiber cells. We performed a detailed analysis of Eph receptor and ephrin ligand mRNA transcripts in whole mouse lenses, epithelial cell fractions, and fiber cell fractions using a new RNA isolation method. We compared control samples with EphA2 knockout (KO) and ephrin-A5 KO samples. Our results revealed the presence of transcripts for 12 out of 14 Eph receptors and 8 out of 8 ephrin ligands in various fractions of lens cells. Using specific primer sets, RT-PCR, and sequencing, we verified the variant of each gene that is expressed, and we found two epithelial-cell-specific genes. Surprisingly, we also identified one Eph receptor variant that is expressed in KO lens fibers but is absent from control lens fibers. We also identified one low expression ephrin variant that is only expressed in ephrin-A5 control samples. These results indicate that the lens expresses almost all Ephs and ephrins, and there may be many receptor–ligand pairs that play a role in lens homeostasis. [ABSTRACT FROM AUTHOR]

Highlights: Tube formation on MatrigelTM and tube formation in co-culture with MSCs are two different stages of angiogenesis. uPA, uPAR, Jagged1, and Notch2 are common upregulated genes for ECs on MatrigelTM, in co-culture and in dividing/migrating cells. EndMT activated at a much greater extent in ECs in a co-culture model than in a MatrigelTM assay. Only in the MatrigelTM assay are the Notch and Hippo pathway-related genes upregulated. A Matrigel-based tube formation assay is a simple and widely accepted 2D angiogenesis model in vitro. Extracellular matrix (EM) proteins and growth factors (GFs) from MatrigelTM exclusively trigger endothelial cell (EC) tubular network (ETN) formation. Co-culture of ECs with mesenchymal stromal cells (MSCs) is another and more reliable in vitro angiogenesis assay. MSCs modulate ETN formation through intercellular interactions and as a supplier of EM and GFs. The aim of the present study was to compare the expression profile of ECs in both models. We revealed upregulation of the uPA, uPAR, Jagged1, and Notch2 genes in dividing/migrating ECs and for ECs in both experimental models at 19 h. The expression of endothelial–mesenchymal transition genes largely increased in co-cultured ECs whereas Notch and Hippo signaling pathway genes were upregulated in ECs on MatrigelTM. We showed that in the co-culture model, basement membrane (BM) deposition is limited only to cell-to-cell contacts in contrast to MatrigelTM, which represents by itself fully pre-assembled BM matrix. We suggest that ETN in a co-culture model is still in a dynamic process due to immature BM whereas ECs in the MatrigelTM assay seem to be at the final stage of ETN formation. [ABSTRACT FROM AUTHOR]

The Eph receptor, a prototypically large receptor protein tyrosine kinase, interacts with ephrin ligands, forming a bidirectional signaling system that impacts diverse brain functions. Eph receptors and ephrins mediate forward and reverse signaling, affecting neurogenesis, axon guidance, and synaptic signaling. While mammalian studies have emphasized their roles in neurogenesis and synaptic plasticity, the Drosophila counterparts are less studied, especially in glial cells, despite structural similarities. Using RNAi to modulate Eph / ephrin expression in Drosophila neurons and glia, we studied their roles in brain development and sleep and circadian behavior. Knockdown of neuronal ephrin disrupted mushroom body development, while glial knockdown had minimal impact. Surprisingly, disrupting ephrin in neurons or glial cells altered sleep and circadian rhythms, indicating a direct involvement in these behaviors independent from developmental effects. Further analysis revealed distinct sleep phenotypes between neuronal and glial knockdowns, underscoring the intricate interplay within the neural circuits that govern behavior. Glia-specific knockdowns showed altered sleep patterns and reduced circadian rhythmicity, suggesting an intricate role of glia in sleep regulation. Our findings challenge simplistic models of Eph/ephrin signaling limited to neuron-glia communication and emphasize the complexity of the regulatory networks modulating behavior. Future investigations targeting specific glial subtypes will enhance our understanding of Eph/ephrin signaling's role in sleep regulation across species. • Eph/ephrin signaling in Drosophila impacts brain development & behavior. • Eph/ephrin knockdown in neurons, but not glia, disrupts mushroom body development. • Both neuronal and glial perturbations of Eph/ephrin alter sleep/circadian rhythms. • Glial knockdown reveals intricate glia-specific role in sleep regulation. [ABSTRACT FROM AUTHOR]

Erythropoietin-producing hepatocellular carcinoma receptors (EPHs) represent the largest family of receptor tyrosine kinases (RTKs). EPH interaction with ephrins, their membrane-bound ligands, holds a pivotal role in embryonic development, while, though less active, it is also implicated in various physiological functions during adult life. In normal hematopoiesis, different patterns of EPH/ephrin expression have been correlated with hematopoietic stem cell (HSC) maintenance and lineage-committed hematopoietic progenitor cell (HPC) differentiation, as well as with the functional properties of their mature offspring. Research in the field of hematologic malignancies has unveiled a rather complex involvement of the EPH/ephrinsignaling pathway in the pathophysiology of these neoplasms. Aberrations in genetic, epigenetic, and protein levels have been identified as possible players implicated both in tumor progression and suppression, while correlations have also been highlighted regarding prognosis and response to treatment. Initial efforts to therapeutically target the EPH/ephrin axis have been undertaken in the setting of hematologic neoplasia but are mainly confined to the preclinical level. To this end, deciphering the complexity of this signaling pathway both in normal and malignant hematopoiesis is necessary.

During orthodontic tooth movement, mechanically induced remodeling occurs in the alveolar bone due to the action of orthodontic forces. The number of factors identified to be involved in mechanically induced bone remodeling is growing steadily. With the uncovering of the functions of neuronal guidance molecules (NGMs) for skeletal development as well as for bone homeostasis, NGMs are now also among the potentially significant factors for the regulation of bone remodeling during orthodontic tooth movement. This narrative review attempts to summarize the functions of NGMs in bone homeostasis and provides insight into the currently sparse literature on the functions of these molecules during orthodontic tooth movement. Presently, four families of NGMs are known: Netrins, Slits, Semaphorins, ephrins and Eph receptors. A search of electronic databases revealed roles in bone homeostasis for representatives from all four NGM families. Functions during orthodontic tooth movement, however, were only identified for Semaphorins, ephrins and Eph receptors. For these, crucial prerequisites for participation in the regulation of orthodontically induced bone remodeling, such as expression in cells of the periodontal ligament and in the alveolar bone, as well as mechanical inducibility, were shown, which suggests that the importance of NGMs in orthodontic tooth movement may be underappreciated to date and further research might be warranted. [ABSTRACT FROM AUTHOR]

Liver cancer is ranked as the second leading cause of cancer-related death across the world, and hepatocellular carcinoma (HCC) comprises nearly 90% of all primary liver cancer cases. However, until now, the pathological mechanisms underlying HCC oncogenesis and development remains largely unclear. Eph receptors and their ephrin ligands (Eph/Ephrin system) are involved in various physiological process, such as embryogenesis, neuronal migration, immune response and vascular development. Recently, emerging evidence has showed that the Eph/Ephrin system also plays an essential role in initiation and development of multiple types of cancer, including liver cancer. The Eph/Ephrin system has been reported to contribute to cellular proliferation, apoptosis, migration, invasion, angiogenesis, stemness and drug/radiotherapy resistance in HCC. Thus, the aim of this review is to summarize the effects and underlying mechanisms of every member of this system in HCC, with special focus on assessing their therapeutic potential as drug targets. [ABSTRACT FROM AUTHOR]

Studies have found that molecular targets that regulate tissue development are also involved in regulating tissue regeneration. Erythropoietin-producing hepatocyte A4 (EphA4) not only plays a guiding role in neurite outgrowth during the development of the central nervous system (CNS) but also induces injured axon retraction and inhibits axon regeneration after spinal cord injury (SCI). EphA4 targets several ephrin ligands (including ephrin-A and ephrin-B) and is involved in cortical cell migration, axon guidance, synapse formation and astrocyte function. However, how EphA4 affects axon regeneration after SCI remains unclear. This study focuses on the effect and mechanism of EphA4-regulated astrocyte function in neuronal regeneration after SCI. Our research found that EphA4 expression increased significantly after SCI and peaked at 3 days post-injury; accordingly, we identified the cellular localization of EphA4 and ephrin-B ligands in neurons and astrocytes after SCI. EphA4 was mainly expressed on the surface of neurons, ephrin-B1 and ephrin-B3 were mainly localized on astrocytes, and ephrin-B2 was distributed on both neurons and astrocytes. To further elucidate the effect of EphA4 on astrocyte function after SCI, we detected the related cytokines secreted by astrocytes in vivo. We found that the levels of neurotrophic factors including nerve growth factor (NGF) and basic fibroblast growth factor (bFGF) increased significantly after SCI (NGF peaked at 3 days and bFGF peaked at 7 days); the expression of laminin and fibronectin increased gradually after SCI; the expression of inflammatory factors [interleukin (IL)-1β and IL-6] increased significantly from 4 h to 7 days after SCI; and the levels of glial fibrillary acidic protein (GFAP), a marker of astrocyte activation, and chondroitin sulphate proteoglycan (CSPG), the main component of glial scars, both peaked at 7 days after SCI. Using a damaged astrocyte model in vitro, we similarly found that the levels of related cytokines increased after injury. Consequently, we observed the effect of damaged astrocytes on neurite outgrowth and regeneration, and the results showed that damaged astrocytes hindered neurite outgrowth and regeneration; however, the inhibitory effect of injured astrocytes on neurite regeneration was reduced following ephrin-B receptor knockdown or inflammatory inhibition at 24 h after astrocyte injury. Our results showed that EphA4 regulates the secretion of neurotrophic factors, adhesion molecules, inflammatory factors and glial scar formation by binding with the ligand ephrin-B located on the surface of astrocytes. EphA4 affects neurite outgrowth and regeneration after SCI by regulating astrocyte function. [ABSTRACT FROM AUTHOR]

The interaction between immune cells and virus-infected targets involves multiple plasma membrane (PM) proteins. A systematic study of PM protein modulation by vaccinia virus (VACV), the paradigm of host regulation, has the potential to reveal not only novel viral immune evasion mechanisms, but also novel factors critical in host immunity. Here, >1000 PM proteins were quantified throughout VACV infection, revealing selective downregulation of known T and NK cell ligands including HLA-C, downregulation of cytokine receptors including IFNAR2, IL-6ST and IL-10RB, and rapid inhibition of expression of certain protocadherins and ephrins, candidate activating immune ligands. Downregulation of most PM proteins occurred via a proteasome-independent mechanism. Upregulated proteins included a decoy receptor for TRAIL. Twenty VACV-encoded PM proteins were identified, of which five were not recognised previously as such. Collectively, this dataset constitutes a valuable resource for future studies on antiviral immunity, host-pathogen interaction, poxvirus biology, vector-based vaccine design and oncolytic therapy. Author summary: Vaccinia virus (VACV) is the vaccine used to eradicate smallpox and an excellent model for studying host-pathogen interactions. Many VACV-mediated immune evasion strategies are known, however how immune cells recognise VACV-infected cells is incompletely understood because of the complexity of surface proteins regulating such interactions. Here, a systematic study of proteins on the cell surface at different times during infection with VACV is presented. This shows not only the precise nature and kinetics of appearance of VACV proteins, but also the selective alteration of cellular surface proteins. The latter thereby identified potential novel immune evasion strategies and host proteins regulating immune activation. Comprehensive comparisons with published datasets provided further insight into mechanisms used to regulate surface protein expression. Such comparisons also identified proteins that are targeted by both VACV and human cytomegalovirus (HCMV), and which are therefore likely to represent host proteins regulating immune recognition and activation. Collectively, this work provides a valuable resource for studying viral immune evasion mechanisms and novel host proteins critical in host immunity. [ABSTRACT FROM AUTHOR]

Neural tube defects (NTDs) are common birth defects with a complex genetic etiology. Mouse genetic models have indicated a number of candidate genes, of which functional mutations in some have been found in human NTDs, usually in a heterozygous state. This study focuses on Ephs-ephrins as candidate genes of interest owing to growing evidence of the role of this gene family during neural tube closure in mouse models. Eph-ephrin genes were analyzed in 31 Malaysian individuals comprising seven individuals with sporadic spina bifida, 13 parents, one twin-sibling and 10 unrelated controls. Whole exome sequencing analysis and bioinformatic analysis were performed to identify variants in 22 known Eph-ephrin genes. We reported that three out of seven spina bifida probands and three out of thirteen family members carried a variant in either EPHA2 (rs147977279), EPHB6 (rs780569137) or EFNB1 (rs772228172). Analysis of public databases shows that these variants are rare. In exome datasets of the probands and parents of the probands with Eph-ephrin variants, the genotypes of spina bifida-related genes were compared to investigate the probability of the gene–gene interaction in relation to environmental risk factors. We report the presence of Eph-ephrin gene variants that are prevalent in a small cohort of spina bifida patients in Malaysian families. [ABSTRACT FROM AUTHOR]

Although the role of microtubule dynamics in cancer progression is well-established, the roles of tubulin isotypes, their cargos and their specific function in the induction and sustenance of cancer stem cells (CSCs) were poorly explored. But emerging reports urge to focus on the transport function of tubulin isotypes in defining orchestrated expression of functionally critical molecules in establishing a stem cell niche, which is the key for CSC regulation. In this review, we summarize the role of specific tubulin isotypes in the transport of functional molecules that regulate metabolic reprogramming, which leads to the induction of CSCs and immune evasion. Recently, the surface expression of GLUT1 and GRP78 as well as voltage-dependent anion channel (VDAC) permeability, regulated by specific isotypes of β-tubulins have been shown to impart CSC properties to cancer cells, by implementing a metabolic reprogramming. Moreover, βIVb tubulin is shown to be critical in modulating EphrinB1signaling to sustain CSCs in oral carcinoma. These tubulin-interacting molecules, Ephrins, GLUT1 and GRP78, are also important regulators of immune evasion, by evoking PD-L1 mediated T-cell suppression. Thus, the recent advances in the field implicate that tubulins play a role in the controlled transport of molecules involved in CSC niche. The indication of tubulin isotypes in the regulation of CSCs offers a strategy to specifically target those tubulin isotypes to eliminate CSCs, rather than the general inhibition of microtubules, which usually leads to therapy resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: Carcinoma associated fibroblasts (CAF) play a critical role in the tumor microenvironment (TME) of prostate cancer (PCa). Ephrin receptors (Eph) and ligands (EFN) have been implicated in distinct types of cancers. Alterations on EphB receptors are frequently found in PCa, but the role of ligands (EFNB1, EFNB2, EFNB3) activation in prostate fibroblasts and consequent effects on PCa is not known. We found increased EFNB ligands in fibroblasts isolated from PCa tissues. In this study, we assessed the effects of elevated stromal EFNB ligands on PCa tumor growth. Increased EFNB1 and EFNB3 expression transformed normal fibroblasts into CAF phenotypes through activation of Src family kinases. The secretome of EFNB-expressing CAF increased PCa cell proliferation and promoted TME remodeling. Overall, EFNB activation in CAF may participate in PCa progression via the release of soluble factors that modulate the surrounding tumor environment, which, in turn, promote prostate tumor growth and invasion. Through stromal-epithelial interactions, carcinoma associated fibroblasts (CAF) play a critical role in tumor growth and progression. Activation of erythrophoyetin-producing human hepatocellular (Eph) receptors has been implicated in cancer. Eph receptor interactions with Ephrin ligands lead to bidirectional signals in the recipient and effector cells. The consequences of continuous reverse Ephrin signaling activation in fibroblasts on prostate cancer (PCa) is unknown. When compared to benign prostate fibroblast, CAF displayed higher expression of Ephrin B1, B2, and B3 ligands (EFNB1, EFNB2, and EFNB3). In this study, we found that continuous activation of EFNB1 and EFNB3 in a benign human prostate stromal cell line (BHPrS1) increased the expression of CAF markers and induced a CAF phenotype. BHPrS1EFNB1 and BHPrS1EFNB3 displayed a pro-tumorigenic secretome with multiple effects on neovascularization, collagen deposition, and cancer cell proliferation, overall increasing tumorigenicity of a premalignant prostate epithelial cell line BPH1 and PCa cell line LNCaP, both in vitro and in vivo. Inhibition of Src family kinases (SFK) in BHPrS1EFNB1 and BHPrS1EFNB3 suppressed EFNB-induced ɑ-SMA (Alpha-smooth muscle actin) and TN-C (Tenascin-C) in vitro. Our study suggests that acquisition of CAF characteristics via SFK activation in response to increased EFNB ligands could promote carcinogenesis via modulation of TME in PCa. [ABSTRACT FROM AUTHOR]

Musculoskeletal sarcomas represent rare heterogenous malignancies of mesenchymal origin that can be divided in two distinct subtypes, bone and soft tissue sarcomas. Current treatment options combine the surgical excision of local tumors and multidrug chemotherapy to prevent metastatic widespread disease. Due to the grim prognosis that usually accompanies such tumors, researchers have attempted to shed light on the molecular pathways implicated in their pathogenesis in order to develop novel, innovative, personalized therapeutic strategies. Erythropoietin-producing human hepatocellular receptors (EPHs) are tyrosine-kinase transmembrane receptors that, along with their ligands, ephrins, participate in both tumor-suppressive or tumor-promoting signaling pathways in bone and soft tissue sarcomas. The EPH/ephrin axis orchestrates cancerous processes such as cell–cell and cell–substrate adhesion and enhances the remodeling of the intracellular cytoskeleton to stimulate the motility and invasiveness of sarcoma cells. The purpose of our study was to review published PubMed literature to extract results from in vitro, in vivo and clinical trials indicative of the role of EPH/ephrin signaling in bone and soft tissue sarcomas. Based on these reports, significant interactions between the EPH/ephrin signaling pathway and a plethora of normal and abnormal cascades contribute to molecular mechanisms enhancing malignancy during sarcoma progression. In addition, EPHs and ephrins are prospective candidates for diagnostic, monitoring and therapeutic purposes in the clinical setting against bone and soft tissue sarcomas. [ABSTRACT FROM AUTHOR]

Uveal melanomas (UMs) comprise the most common primary intraocular malignancies in adults, with the eye representing the second most common site for melanoma, following the skin. Prognosis remains poor, with approximately half of the cases presenting with metastatic disease at the time of diagnosis. Erythropoietin-producing human hepatocellular receptors (EPHs) comprise the largest known family of tyrosine receptors, in which, along with their ligands, ephrins, play an important role in a plethora of processes in human physiology, and are implicated in key steps of carcinogenesis. In the present study, EPHA2, EPHA4, and EPHA6 immunohistochemical expressions were investigated in UM tissues and further correlated to a multitude of clinicopathological parameters, including disease stage and patients' overall survival (OS). High levels of EPHA2 expression were significantly associated with increased tumor vertical thickness (p = 0.03) and the presence of intrascleral involvement (p = 0.05), whereas high EPHA6 nuclear expression was associated with older age at diagnosis (p = 0.03) and absence of retinal detachment (p = 0.05). In a multivariate survival analysis, increased EPHA4 expression was associated with shortened OS along with the presence of metastasis (p < 0.001) and monosomy 3 (p = 0.02). In a separate model, the concurrent overexpression of at least two of the investigated EPHs (HR = 14.7, p = 0.03) also proved to be an independent poor prognostic factor. In conclusion, our results implicate these specific members of the EPHA group as potential biomarkers for disease prognosis as well as possible targets for the development of novel therapeutic interventions. [ABSTRACT FROM AUTHOR]

Exosomes are cell-secreted nanoparticles containing various molecules including small vesicles, microRNAs (miRNAs), messenger RNAs or bioactive proteins which are thought to be of paramount importance for intercellular communication. The unique effects of exosomes in terms of cell penetration capacity, decreased immunogenicity and inherent stability, along with their key role in mediating information exchange among tumor cells and their surrounding tumor microenvironment (TME), render them a promising platform for drug targeted delivery. Compared to synthetic drugs, exosomes boast a plethora of advantages, including higher biocompatibility, lower toxicity and increased ability of tissue infiltration. Nevertheless, the use of artificial exosomes can be limited in practice, partly due to their poor targeting ability and partly due to their limited efficacy. Therefore, efforts have been made to engineer stem cell-derived exosomes in order to increase selectiveness and effectivity, which can then become loaded with various active substances depending on the therapeutic approach followed. Erythropoietin-producing human hepatocellular receptors (EPHs), along with their ligands, the EPH family receptor interacting proteins (ephrins), have been extensively investigated for their key roles in both physiology and cancer pathogenesis. EPHs/ephrins exhibit both tumorigenic and tumor suppressing properties, with their targeting representing a promising, novel therapeutic approach in cancer patients' management. In our review, the use of ephrin-loaded exosomes as a potential therapeutic targeted delivery system in cancer will be discussed. [ABSTRACT FROM AUTHOR]

Müller cells (MC) are considered dormant retinal progenitor cells in mammals. Previous studies demonstrated ephrin-As act as negative regulators of neural progenitor cells in the retina and brain. It remains unclear whether the lack of ephrin-A2/A3 is sufficient to promote the neurogenic potential of MC. Here we investigated whether the MC is the primary retinal cell type expressing ephrin-A2/A3 and their role on the neurogenic potential of Müller cells. In this study, we showed that ephrin-A2/A3 and their receptor EphA4 were expressed in retina and especially enriched in MC. The level of ephrinAs/EphA4 expression increased as the retina matured that is correlated with the reduced proliferative and progenitor cell potential of MC. Next, we investigated the proliferation in primary MC cultures isolated from wild-type and A2–/– A3–/– mice by 5-ethynyl-2′-deoxyuridine (EdU) incorporation. We detected a significant increase of EdU+ cells in MC derived from A2–/– A3–/– mice. Next, we investigated the role of ephrin-A2/A3 in mice undergoing photoreceptor degeneration such as Rhodopsin knockout (Rho–/–) mice. To further evaluate the role of ephrin-A2/A3 in MC proliferation in vivo, EdU was injected intraperitoneally to adult wild-type, A2–/– A3–/– , Rho–/– and Rho–/– A2–/– A3–/– mice and the numbers of EdU+ cells distributed among different layers of the retina. EphrinAs/EphA4 expression was upregulated in the retina of Rho–/– mice compared to the wild-type mice. In addition, cultured MC derived from ephrin-A2–/– A3–/– mice also expressed higher levels of progenitor cell markers and exhibited higher proliferation potential than those from wild-type mice. Interestingly, we detected a significant increase of EdU+ cells in the retinas of adult ephrin-A2–/– A3–/– mice mainly in the inner nuclear layer; and these EdU+ cells were co-localized with MC marker, cellular retinaldehyde-binding protein, suggesting some proliferating cells are from MC. In Rhodopsin knockout mice (Rho–/– A2–/– A3–/– mice), a significantly greater amount of EdU+ cells were located in the ciliary body, retina and RPE than that of Rho–/– mice. Comparing between 6 and 12 weeks old Rho–/– A2–/– A3–/– mice, we recorded more EdU+ cells in the outer nuclear layer in the 12-week-old mice undergoing severe retinal degeneration. Taken together, Ephrin-A2/A3 are negative regulators of the proliferative and neurogenic potentials of MC. Absence of ephrin-A2/A3 promotes the migration of proliferating cells into the outer nuclear layer and may lead to retinal cell regeneration. All experimental procedures were approved by the Animal Care and Use Committee at Schepens Eye Research Institute, USA (approval No. S-353-0715) on October 24, 2012.

Gynecological cancers represent some of the most common types of malignancy worldwide. Erythropoietin-producing hepatocellular receptors (EPHs) comprise the largest subfamily of receptor tyrosine kinases, binding membrane-bound proteins called ephrins. EPHs/ephrins exhibit widespread expression in different cell types, playing an important role in carcinogenesis. The aim of the current review was to examine the dysregulation of the EPH/ephrin system in gynecological cancer, clarifying its role in ovarian, endometrial, and cervical carcinogenesis. In order to identify relevant studies, a literature review was conducted using the MEDLINE and LIVIVO databases. The search terms ephrin, ephrin receptor, ovarian cancer, endometrial cancer, and cervical cancer were employed and we were able to identify 57 studies focused on gynecological cancer and published between 2001 and 2021. All researched ephrins seemed to be upregulated in gynecological cancer, whereas EPHs showed either significant overexpression or extensive loss of expression in gynecological tumors, depending on the particular receptor. EPHA2, the most extensively studied EPH in ovarian cancer, exhibited overexpression both in ovarian carcinoma cell lines and patient tissue samples, while EPHB4 was found to be upregulated in endometrial cancer in a series of studies. EPHs/ephrins were shown to exert their role in different stages of gynecological cancer and to influence various clinicopathological parameters. The analysis of patients' gynecological cancer tissue samples, most importantly, revealed the significant role of the EPH/ephrin system in the development and progression of gynecological cancer, as well as overall patient survival. In conclusion, the EPH/ephrin system represents a large family of biomolecules with promising applications in the fields of diagnosis, prognosis, disease monitoring, and treatment of gynecological cancer, with an established important clinical impact. [ABSTRACT FROM AUTHOR]

• We tested TDP-43 expression in lateral motor column (LMC) neurons growing into a limb. • TDP-43 function loss/gain redirects LMC axon trajectory selection w/ opposite effects. • TDP-43 level changes LMC explant neurite growth preference against ephrin ligands. • Other ligand types including Netrin-1 and Semaphorin3 F were not involved in TDP-43-mediated LMC pathfinding. • TDP-43 is essential for the ephrin-mediated LMC axon trajectory into the limb. During the neural circuit formation, neuronal growth cones must be guided precisely to their neuronal or muscle targets, which can be achieved by the activation of membrane-bound guidance receptors at the periphery. However, the mechanisms that regulate the temporal availability of these receptors remain largely unknown. TAR DNA binding protein-43 (TDP-43) has been proposed to bind with the mRNAs of guidance receptors, thus prompting us to investigate its role in axon guidance of the spinal lateral motor column (LMC) neurons into the limb mesenchyme. We first identified the TDP-43 expression in the LMC neurons at the stage of axons growth into the limb using in situ mRNA hybridization. The loss and gain of TDP-43 function in chick LMC neurons redirected their axon trajectory with opposite effects. In mice, a spinal motor neuron-specific TDP-43 deletion led to the misrouting of LMC axons. Further, ectopic TDP-43 expression increased EphB protein levels in LMC neurons, suggesting that TDP-43 mediates LMC pathfinding by regulating EphB expression. Finally, TDP-43 levels influenced the growth preference of LMC neurites against ephrin-B, but not Netrin-1 and Semaphorin ligands. Our results demonstrate that TDP-43 is essential for the ephrinB:EphB signaling-mediated axon trajectory selection of LMC subtypes into the limb. [ABSTRACT FROM AUTHOR]