Search Results (144)

SASH1 (SAM [sterile alpha motif] and SH3 [SRC-homology-3] domain-containing protein 1) is a multidomain scaffold implicated in pigmentation, innate immunity, receptor signaling, cytoskeletal dynamics, vascular biology, and tumor suppression. Although genetic and expression studies link SASH1 dysfunction to diverse diseases, a unifying mechanistic framework has remained elusive. Here, we synthesize current knowledge of SASH1 structure, interaction networks, and biological functions across cell types and disease contexts. SASH1 contains an intrinsically disordered SPIDER (SLy Proteins Associated Disordered Region), an SH3 domain, two SAM domains, and multiple linear motifs; together, these elements mediate interactions with EphA8 (ephrin type-A receptor 8), β-arrestin 1, TRAF6 (TNF receptor-associated factor 6), CRKL (CRK-like proto-oncogene), IQGAP1 (IQ-motif-containing GTPase-activating protein 1), cortactin, and TNKS2 (tankyrase-2). We propose that SASH1 functions as a context-dependent multi-docking scaffold that organizes signaling architecture. Its modular domains, intrinsically disordered regions, and dual SAM domains enable flexible, multivalent interactions with partners that can be grouped into three functional modules: receptor regulation, intracellular signaling, and cytoskeletal organization. Notably, many SASH1 partners are themselves scaffold or adaptor proteins, allowing integration into pre-existing networks in a hierarchical ‘scaffold-of-scaffolds’ manner. Through selective partner recruitment, SASH1 links cell-surface receptor inputs to downstream signaling pathways and cytoskeletal remodeling. This model provides a mechanistic framework for how SASH1 drives diverse, cell-type-specific outputs across physiology and disease, while revealing broader principles by which multidomain scaffolds encode cellular behavior. Full article

The heterogeneity of tumor cells facilitates their dynamic adaptation to tumor microenvironmental pressures throughout progression. Nevertheless, the mechanisms underlying intercellular communication and transformation among heterogeneous tumor cells remain inadequately understood. In this study, we indicate that Ephrin type-A receptor 2 (EphA2) is heterogeneously expressed in gastric cancer (GC) tumor cells, with those exhibiting elevated EphA2 (EphA2^High) expression demonstrating enhanced migratory and invasive capabilities. EphA2^High cells facilitate the transfer of EphA2 via exosomes, which subsequently localize on the membrane of EphA2^Low cells, thereby activating the ERK signaling pathway in a ligand-independent manner. This process promotes the transformation of EphA2^Low cells and contributes to the progression of GC. An investigation into the correlation between serum levels and tumor metastasis in patients with GC revealed that those with lymph node metastasis exhibited higher levels of serum exosomal EphA2. This study elucidates the process of dominant group formation within heterogeneous tumor cells and suggests the viability of exosomal EphA2 as a potential biomarker for further clinical investigation. Full article

Background: Thymic epithelial tumors (TETs) are the most common primary neoplasms of the anterior mediastinum and present a dual classification challenge, namely anatomical staging according to the Masaoka–Koga system and histological risk stratification according to the World Health Organization (WHO) classification. Both tasks rely on expert pathological assessment and may be affected by interobserver variability. This study applied supervised machine learning (ML) to quantitative immunohistochemical (IHC) H-score profiles to predict Masaoka–Koga stage and WHO risk group in TETs. Methods: Logistic regression (LR) and XGBoost were applied to 19 biomarkers, including cellular localization, across two parallel analyses. Masaoka–Koga stage prediction was performed in 81 patients, including 59 early-stage and 22 advanced-stage cases, using the Synthetic Minority Oversampling Technique (SMOTE) across 100 train/test splits. WHO risk group prediction was performed in 89 patients, including 45 low-risk and 44 high-risk tumors, without oversampling. A cross-endpoint analysis applied the optimal Masaoka–Koga model to the WHO endpoint. Results: LR consistently outperformed XGBoost. The optimal Masaoka–Koga model combined Eph receptor A6 (EphA6) membranous, Yes-associated protein (YAP) nuclear, and histone deacetylase 4 (HDAC4) cytoplasmic H-scores, achieving an area under the curve (AUC) of 0.756. The optimal WHO model combined transcriptional coactivator with PDZ-binding motif (TAZ) cytoplasmic, EphA6 membranous, and YAP nuclear H-scores, achieving an AUC of 0.936. The Masaoka–Koga triad predicted WHO risk group with an AUC of 0.901. No tetrad improved trivariate performance. Conclusions: IHC H-score profiling combined with supervised ML identifies biologically interpretable candidate signatures for TET classification, although prospective external validation is required before clinical application. Full article

Ultraviolet B (UVB) radiation-induced corneal injury poses a significant public health challenge. However, its underlying molecular mechanisms remain incompletely understood, hindering the development of effective interventions. This study identified a key molecular pathway in UVB-induced corneal damage, revealing that UVB exposure triggers a rapid intracellular burst of reactive oxygen species (ROS), which in turn upregulates and aberrantly activates the receptor tyrosine kinase Ephrin type-A receptor 2 (EphA2), thereby collectively accelerating DNA damage and photoaging in corneal epithelial cells. Based on this mechanism, we developed the natural compound Penicophenone F (PP-F), which was screened and identified from the Arctic fungus Penicillium sp. MYA5, as a novel therapeutic strategy against UVB-induced corneal damage. In vitro and in vivo experiments suggest that PP-F may mediate its therapeutic effects via a dual mechanism. On one hand, it may counteract UVB damage by modulating ROS levels through regulation of endogenous antioxidant enzymes, inhibiting aberrant EphA2 activation, and promoting cellular proliferation and DNA repair. On the other hand, it may upregulate IRF6 to activate the cGAS pathway, which could enhance antioxidant defenses and significantly contribute to the restoration of epithelial barrier integrity and overall corneal physiology. These results underscore the safety and potential of PP-F in treating UVB-induced corneal damage and other oxidative stress-related ocular surface diseases. Full article

Fungal β-1,3-glucans are structurally conserved polysaccharide components of the fungal cell wall that exhibit potent immunomodulatory activity. These molecules are recognized by pattern recognition receptors, Toll-like receptors, complement receptor 3, lactosylceramide, scavenger receptors, and EphA2. Binding of β-1,3-glucans through these receptors triggers coordinated innate and adaptive immune responses such as cytokine production, phagocytosis, and trained immunity. In addition to receptor-mediated immune activation, dietary β-1,3-glucans function as fermentable prebiotic fibers that modulate gut microbiota composition, increase short-chain fatty acid production, and strengthen epithelial barrier integrity. These combined immunological and microbiome-mediated effects position β-1,3-glucans as key regulators of gut homeostasis. Preclinical and emerging clinical evidence supports broad therapeutic potential across multiple disease domains, including inflammatory bowel disease, metabolic disorders, respiratory infections, and cancer. In oncology, β-1,3-glucans enhance anti-tumor immunity, improve responses to monoclonal antibodies and chemotherapy, and serve as promising adjuvants in vaccine-based strategies. Additionally, β-1,3-glucan is widely used as a biomarker for invasive fungal infections and represents a validated target of antifungal therapies such as echinocandins. Despite these advances, clinical translation remains limited by heterogeneity in glucan source, structure, and formulation, as well as a lack of appropriately powered, standardized human clinical trials. Future efforts should focus on clarifying mechanisms of action, as well as rigorous clinical evaluation, to fully define the therapeutic utility of fungal β-1,3-glucans. Full article

During development, tissues or organs are organized into distinct cell populations that do not intermix. The precise spatiotemporal arrangement of these populations establishes tissue boundaries and ensures proper morphogenesis. Signaling between membrane-bound Eph receptors and their ephrin ligands underlies the formation of multiple developmental boundaries, including those between germ layers, rhombomeres, and eye fields. Moreover, accumulating evidence indicates that actomyosin contractility serves as an important mechanical driver of Eph/ephrin-cell segregation and boundary formation. However, the mechanism by which Eph/ephrin signaling regulates actomyosin contractility have received relatively limited attention in previous reviews, particularly in the context of boundary sharpening. In this review, we focus on the interplay between Eph/ephrin signaling and actomyosin contractility and discuss how this interaction contributes to cell segregation and boundary formation. Full article

Erythropoietin-producing hepatocellular receptor A2 (EphA2) has emerged as a key mediator that promotes tumor malignant progression. EphA2 overexpression and its non-canonical signaling lead to oncogenic transformation, metabolic reprogramming, resistance to treatments, and metastasis. Therefore, strategies targeting EphA2 have been evaluated in clinical trials. However, the clinical effects were not sufficient. An anti-EphA2 monoclonal antibody (mAb), Ea₂Mab-7 (mouse IgG₁, κ), demonstrated high affinity and specificity among Eph receptors. In this study, we produced recombinant class-switched Ea₂Mab-7 variants, including Ea₂Mab-7-mG_2a (mouse IgG_2a) and Ea₂Mab-7-hG₁ (human IgG₁). Both Ea₂Mab-7-mG_2a and Ea₂Mab-7-hG₁ recognized human triple-negative breast cancer MDA-MB-231, pancreatic cancer MIA PaCa-2, and colorectal cancer HCT-15 in flow cytometry. Furthermore, both Ea₂Mab-7-mG_2a and Ea₂Mab-7-hG₁ exerted significant antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity against these tumors. In mouse xenograft models of breast, pancreatic, and colorectal cancers, both mAbs demonstrated antitumor activity. These results indicate the potential of Ea₂Mab-7 variants for the treatment of EphA2-positive cancers. Full article

Successful organ regeneration depends on coordinated cell-to-cell communication mediated by ligand–receptor interactions that regulate proliferation, differentiation, and axonal guidance. Sea cucumbers, particularly Holothuria glaberrima, exhibit remarkable regenerative capacity following evisceration, regenerating their complete intestinal system within weeks. To identify molecular signals orchestrating these events, we characterized five ligand–receptor groups of axonal guidance molecules (Netrin/UNC5-DSCAM, Ephrin/Eph receptors, Semaphorin/Plexin, RGMα/Neogenin, and SLIT/ROBO) using transcriptomic databases from regenerating intestines and the radial nerve cord. Comparative analyses confirmed these as highly conserved orthologs, retaining characteristic structural domains essential for guidance signaling. Multiple alternatively spliced isoforms were detected, with tissue-specific variants suggesting functional diversification. Differential gene expression analysis across intestinal regeneration stages (12 h to 21 days post-evisceration) revealed distinct temporal patterns: Netrin-1 showed significant upregulation at 7–14 days post-evisceration, coinciding with nerve fiber invasion into the intestinal anlage, while the Ephrin, Semaphorin, and SLIT–ROBO pathways exhibited late-stage expression associated with luminal tissue formation. Single-cell RNA sequencing from 9-dpe regenerating intestines localized Netrin to coelomic epithelial cells and UNC5B to differentiating epithelial cells, with CellChat analysis predicting strong epithelial-to-epithelial signaling. These findings strongly suggest that axonal guidance molecules play dual roles during intestinal regeneration: directing neural innervation in early-to-mid stages and orchestrating tissue boundary formation at later stages. Full article

Uveal melanoma (UVM) is a rare cancer that represents the second most common melanoma (after the cutaneous) and the most common primary intraocular malignancy in adults. Despite recent advances in the understanding of UVM pathogenesis, its prognosis remains unchanged, with half of patients dying because of liver metastasis. Erythropoietin-producing human hepatocellular receptors (EPHs) constitute the largest known family of tyrosine receptors, and, along with their ligands, EFNs, regulate key physiological processes and are implicated in cancer pathogenesis. In this study, we used open-access web bioinformatics platforms to explore and analyze big datasets provided by The Cancer Genome Atlas (TCGA) UVM cohort of patients. We profiled the genomic alterations present in a subset of UVM patients, highlighting a likely pathogenic deep deletion of EPHA7. Survival analysis showed that overexpression levels of EPHA4, EPHA5, EPHA8, EPHB2, and EFNB2 are significantly associated with poor overall survival. Additionally, high expression levels of EPHA4, EPHA5, EPHA7, EPHA8, EPHB2, EFNA2, and EFNB2 correlate with reduced progression-free interval and disease-free survival. Finally, we identified the EPHs (EPHA2, EPHA4, EPHA8, and EPHB4) and EFNs (EFNA1, EFNA3, EFNA4, and EFNB2) that are significantly overexpressed in the aggressive epithelioid histological subtype and revealed that the majority of EPHs/EFNs are overexpressed in metastatic disease. In conclusion, our results highlight that a subset of EPHs and EFNs may be associated with worse clinical outcomes (EPHA4, EPHA5, EPHA7, EPHA8, EPHB2, EFNA2, and EFNB2), and an aggressive histological subtype (EPHA2, EPHA4, EPHA8, EPHB4, EFNA1, EFNA3, EFNA4, and EFNB2). The potential correlation of these genes with clinicopathological parameters of UVM need to be evaluated and validated with bioinformatic and experimental approaches in well-characterized cohorts of UVM patients. Full article

Inflammation underpins pulmonary disease progression during tobacco smoke exposure, which may culminate in irreversible pulmonary disease. While primary smoke poses a notable risk, nearly half of the US population is also susceptible due to frequent exposure to secondhand smoke (SHS). In the present study, we assessed the potential role of VYN202, a novel small molecular bromodomain and extra-terminal inhibitor, as a possible means of attenuating SHS-mediated inflammation. We exposed wild-type mice to an acute time course of room air (RA), SHS via a nose-only delivery system (Scireq Scientific, Montreal, Canada), or to both SHS and 10 mg/kg VYN202 (efficacious dose from prior inflammatory models) via oral gavage three times a week. Specific smoke exposure delivery to mice involved SHS from two cigarettes over 10 min, equilibration in room air for 10 min, followed by exposure to SHS from one cigarette for an additional 10 min, for a total SHS exposure of 20 min per day, five days a week for 30 days. We evaluated leukocyte abundance and the secretion of inflammatory mediators in bronchoalveolar lavage fluid (BALF). We also assessed general morphology via histology staining and the activation of receptor tyrosine kinase (RTK) family members. While standard hematoxylin and eosin (H&E) staining resulted in unchanged morphology, SHS-mediated increases in BALF protein abundance, total cellularity, and percent PMNs were attenuated with concomitant administration of VYN202. We also discovered SHS-induced activation of RTKs that were pro-inflammatory (JAK1, JAK3, ABL1, and ACK1), as well as RTKs related to endothelial and vascular remodeling (VEGFR3, VEGFR2, EphB4, EphB6, and FAK). Furthermore, inflammatory cytokines including GCSF, IFN-γ, IL-12p70, IL-17A, LIX, and TNF-α were all augmented by SHS exposure. Despite SHS exposure, each of these RTKs and cytokines/chemokines was significantly attenuated by VYN202. In summary, inflammatory responses induced by SHS exposure were mitigated by VYN202. These data reveal fascinating potential for the utility of VYN202 in lessening smoke-induced pulmonary exacerbations. Full article

ADAM10 is a transmembrane metalloprotease that regulates diverse signalling functions via the shedding of membrane protein ectodomains, and is implicated in tumour development, including glioblastoma multiforme (GBM) and gastrointestinal (GI) cancers, where high ADAM10 expression is associated with poor prognosis. We assessed the role of ADAM10 by gene knockout (KO) in U251 GBM cells, and its effects on protein shedding and protein expression on cell proliferation and on the growth of tumour xenografts in mice. The growth of tumours was severely delayed, relative to modest effects on proliferation in vitro, suggesting roles particularly in the context of the tumour microenvironment (TME). Proteomics analysis of KO cell-conditioned medium showed decreased levels of known ADAM10 targets such as Notch and Eph receptors and ligands, as well as other proteins involved in cell–cell adhesion, migration, signalling, metabolism, differentiation, and development, including angiogenesis. KO cell and tumour lysate analysis also showed modulation of proteins associated with metabolic and catalytic activity, cell–matrix organisation and differentiation. Similar effects were also observed in the SW620 colon cancer model, indicating broader significance. Furthermore, expression of the associated protein sets also correlated with ADAM10 expression in human GBM and colon cancer specimens (TCGA datasets), indicating clinical relevance. Collagens and proteins associated with matrix deposition and fibril organisation were notably reduced in ADAM10 KO GBM tumours, and histology confirmed decreased collagen fibrils and blood vessels. Unexpectedly, increased chondrocyte differentiation was evident in ADAM10 KO U251 tumours, suggesting a role for ADAM10 in maintaining an undifferentiated phenotype in vivo. Together, our data indicate the importance of ADAM10 in diverse signalling mechanisms in tumours and the TME that promote tumour development. Full article

Background: Craniofrontonasal dysplasia (CFND) is an X-linked developmental disorder caused by mutations in the EFNB1 gene located on chromosome Xq13. This gene encodes ephrin-B1, a ligand for Eph receptors, which is involved in cell signaling pathways and the development of the nervous and vascular systems, as well as facial and cranial structures. Paradoxically, the syndrome manifests with greater severity in heterozygous females, whereas hemizygous males typically present with mild or no abnormalities. Methods and Results: We report the case of a late preterm female neonate with dysmorphic features at birth, who subsequently developed necrotizing enterocolitis (NEC) caused by thrombosis of the superior mesenteric artery. Extensive bowel resection led to short bowel syndrome, resulting in cholestatic liver disease, malabsorption, and growth impairment. Array-comparative genomic hybridization (a-CGH) analysis identified a ~791 Kb microduplication at Xq13.1, encompassing the EFNB1 gene, confirming the diagnosis of CFND. She was enrolled in a multidisciplinary follow-up program and, at 2 years of age, presents with marked growth and neurodevelopmental delay. Conclusions: This report describes a rare association between CFND and NEC caused by superior mesenteric artery thrombosis. To the best of our knowledge, no previously reported cases of CFND associated with thrombosis or thrombosis-related conditions, including NEC, have been identified. This is based on a literature review (2004–2025) performed using PubMed and Scopus, and limited to English-language case reports and reviews. Full article

Eph receptor B2 (EphB2) overexpression is associated with poor clinical outcomes in various tumors. EphB2 is involved in malignant tumor progression through the promotion of invasiveness and metastasis. Genetic and transcriptome analyses implicated that EphB2 is a therapeutic target for specific tumor types. A monoclonal antibody (mAb) is one of the essential therapeutic strategies for EphB2-positive tumors. We previously developed an anti-EphB2 mAb, Eb₂Mab-12 (IgG₁, kappa), by immunizing mice with EphB2-overexpressed glioblastoma. Eb₂Mab-12 specifically reacted with the EphB2-overexpressed Chinese hamster ovary-K1 (CHO/EphB2) and some cancer cell lines in flow cytometry. In this study, we engineered Eb₂Mab-12 into a mouse IgG_2a type (Eb₂Mab-12-mG_2a) and a human IgG₁-type (Eb₂Mab-12-hG₁) mAb. Eb₂Mab-12-mG_2a and Eb₂Mab-12-hG₁ retained the reactivity to EphB2-positive cells and exerted antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity in the presence of effector cells and complements, respectively. In CHO/EphB2, triple-negative breast cancer, and lung mesothelioma xenograft models, both Eb₂Mab-12-mG_2a and Eb₂Mab-12-hG₁ exhibited potent antitumor efficacy. These results indicated that Eb₂Mab-12-derived mAbs could be applied to mAb-based therapy against EphB2-positive tumors. Full article

Background: EphA2 is a receptor tyrosine kinase that contributes to tumor growth and metastasis and has been identified as a viable target for many solid cancers. Investigating EphA2’s impact on the host immune system may advance our understanding of tumor immune evasion and the consequences of targeting EphA2 on the tumor microenvironment. Methods: Here, we examine how tumor-specific EphA2 affects the activation and infiltration of immune cell populations and the cytokine and chemokine milieu in murine models of non-small cell lung cancer (NSCLC). Results: Although EphA2 overexpression in NSCLC cells did not display proliferative advantage in vitro, it conferred a growth advantage in vivo. Analysis of lung tumor infiltrates via flow cytometry revealed decreased natural killer and T cells in the EphA2-overexpressing tumors, as well as increased myeloid populations, including tumor-associated macrophages (TAMs). T-cell activation, particularly in CD8+ T cells, was decreased, while PD-1 expression was increased. These changes were accompanied by increased monocyte-attracting chemokines, specifically CCL2, CCL7, CCL8, and CCL12, and immunosuppressive proteins TGF-β and arginase 1 in RNA expression analyses. Conclusions: Our studies suggest EphA2 on tumor cells recruits monocytes and promotes their differentiation into TAMs that likely inhibit the activation and infiltration of cytotoxic lymphocytes, promoting tumor immune escape. Full article

Stage IV colorectal cancer has a poor prognosis, and liver metastases are prone to recurrence, even after resection. This study aimed to identify common cancer antigens, using immunohistochemical staining, as promising targets for antigen-specific immunotherapies in colorectal cancer. We analyzed expression levels and intracellular localization of seven common cancer antigens, CLDN1, EphB4, LAT1, FOXM1, HSP105α, ROBO1, and SPARC, and human leukocyte antigen (HLA) class I via immunohistochemical staining of 85 surgical specimens from primaries and liver metastases. Staining intensity and positive staining were scored to evaluate antigen expression. In 25 primaries, seven cancer antigens were expressed in 88–96% of cases, while HLA class I was expressed on the cell membrane in 80.0% of cases. In 60 liver metastases, FOXM1 and SPARC expression were approximately half that observed in the primaries. Other antigens and HLA class I were highly expressed in both. Most of the primaries and liver metastases may benefit from chimeric antigen receptor-T cell therapy targeting CLDN1, EphB4, and LAT1. Cases with high HLA class I expression may be suitable for vaccine-based and T cell receptor-T cell therapy targeting CLDN1, EphB4, LAT1, FOXM1, HSP105α, ROBO1, and SPARC for primaries and targeting antigens, excluding FOXM1 and SPARC, for liver metastases. Full article