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PubMed2026

NOTCH3 Internal Tandem Duplication Defines a Novel Oncogenic Activation Mechanism of NOTCH Signaling.

NOTCH signaling is activated in tumors through multiple mechanisms, including mutations, gene rearrangements, and gene amplification. We report a novel activation mechanism, an internal tandem duplication (ITD) near the NOTCH3 negative regulatory region (NRR), found in a myogenic mesenchymal neoplasm. This 17-amino acid residue duplication disrupts the tightly autoinhibited structure surrounding the S2 cleavage site, resulting in ligand-independent S2 cleavage and constitutive pathway activation, as demonstrated by increased expression of the NOTCH3 target gene HES1. Cells expressing NOTCH3-ITD showed increased nuclear localization of the receptor and exhibited malignant phenotypes, including enhanced proliferation and migration. Together, these findings support the oncogenic role of NOTCH3-ITD.

Receptor, Notch3↗

PubMed2025

A model of Notch signalling control of angiogenesis: Evidence of a role for Notch ligand heterodimerization.

The ubiquitous Notch receptor signalling network is essential for tissue growth and maintenance. Operationally, receptor activity is regulated by two principal, counterposed mechanisms: intercellular Notch transactivation triggered by interactions between receptors and ligands expressed in neighbouring cells; intracellular cis inhibition mediated by ligands binding to receptors expressed in the same cell. Moreover, different Notch receptor/ligand combinations are known to elicit distinct molecular and cellular responses, and together, these phenomena determine the strength, the duration and the specificity of Notch receptor signalling. To date, it has been assumed that these processes involve discrete ligand homomers and not heteromeric complexes composed of more than one ligand species. In this study, we explore the molecular basis of the opposing actions of the Notch ligands, DLL4 and JAG1, which control angiogenic sprouting. Through a combination of experimental approaches and mathematical modelling, we provide evidence that two mechanisms could underpin this process: 1) DLL4 rather than JAG1 induces efficient Notch1 receptor transactivation; 2) JAG1 directly blocks DLL4-dependent cis-inhibition of Notch signalling through the formation of a JAG1/DLL4 complex. We propose a new model of Notch signalling that recapitulates the formation of tip and stalk cells, which is necessary for sprouting angiogenesis.

Signal Transduction↗

PubMed2025

Cetobacterium somerae ZNN-1 promotes goblet cell differentiation through glutamine-mediated Notch signaling suppression.

INTRODUCTION: The gut microbiota acts as a crucial mediator in the interaction between the diet components and the host metabolism. However, the molecular mechanism by which the gut microbiota adapts to dietary components and subsequently regulates host physiological responses remains unclear. OBJECTIVES: This study aimed to investigate the response of gut microbiota to a plant-based protein diet (soybean meal, SM) and the effects of gut microbiota on host intestinal barrier function, along with the underlying mechanisms in a fish model. METHODS: Histopathological examination, and transepithelial electrical resistance test were used to evaluate the effects of Cetobacterium somerae on intestinal barrier function. Potential molecular mechanisms were validated by integrating whole-genome sequencing, microbiota composition sequencing, transcriptomics, and metabolomics, and utilizing in vitro cell models and mouse-derived organoid models. RESULTS: The results revealed that the SM diet significantly increased the abundance of Cetobacterium somerae in fish. Administration of C.somerae ZNN-1, a dominant strain isolated from the intestine of fish fed with the SM diet, enhanced the intestinal barrier function, particularly increasing the number of goblet cells in the intestine. Whole genome analysis of C. somerae ZNN-1 showed carbohydrate metabolism-associated genes were the most abundant in its metabolic modules. C.somerae ZNN-1 supplementation significantly inhibited the Notch signaling pathway in fish intestine. Metabolomics analysis revealed that administration of C.somerae ZNN-1 increased the glutamine level in fish gut. In vitro experiments demonstrated that glutamine regulated the differentiation of goblet cell by inhibiting the Notch signaling pathway in both human intestinal epithelial cell model and mouse intestinal organoid model. CONCLUSION: C. somerae served as a key bacterium adapted to soybean meal-derived carbohydrates, and it promoted goblet cell differentiation by inhibiting the Notch pathway. This study provides a new perspective for unraveling the interaction mechanisms among diet components, intestinal microbiota and host health.

Animals↗

PubMed2026

Somatic mutations reveal hyperactive Notch signaling in prurigo nodularis.

Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by pruritic skin nodules of unknown etiology. Little is known about genetic changes in PN pathogenesis, particularly somatic events, which are often implicated in inflammatory conditions. We thus performed whole-exome sequencing on 54 lesional and nonlesional skin biopsies from 17 patients with PN and 10 patients with atopic dermatitis (AD) for comparison. Somatic mutational analysis revealed that PN lesional skin harbors recurrent somatic mutations in fibrotic, neurotropic, and cancer-associated genes that are absent in adjacent PN nonlesional skin. Nonsynonymous mutations were most frequently present in NOTCH1 and the Notch signaling pathway, a key regulator of cellular proliferation and tissue fibrosis. In contrast, NOTCH1 mutations were absent in AD. Somatic copy-number analysis, combined with expression data, identified recurrently deleted and downregulated genes in PN lesional skin, which are associated with axonal guidance and extension. Follow-up immunofluorescence validation demonstrated increased NOTCH1 expression in PN lesional skin fibroblasts and increased Notch signaling in PN lesional dermis. Finally, a multicenter analysis revealed increased risk of NOTCH1-associated diseases in patients with PN. In characterizing the somatic landscape of PN, this study highlights the potential role of Notch pathway dysregulation in PN pathogenesis and fibrosis.

Humans↗

PubMed2026

Multidimensional Proteomics Reveals the Pro-apoptotic Mechanism of Platycodin D: Targeting RFC4 to Regulate the Notch Signaling Axis in Non-Small Cell Lung Cancer.

Platycodin D (PD), a major bioactive saponin isolated from the traditional Chinese medicine Platycodon grandiflorus, has shown promising therapeutic potential against non-small cell lung cancer (NSCLC). However, the functional mechanisms of PD in NSCLC progression remains unclear. This study aimed to explore the pharmacological mechanism of PD against NSCLC. Thermal proteome profiling approach, molecular docking, cellular thermal shift assay and peptide-centric local stability assay were employed to identify the potential binding target of PD. Subsequent Western Blot and immunoprecipitation-Western Blot experiments were conducted to investigate the downstream signaling pathways of the target. Furthermore, proteomic and ubiquitinomic profiling of PD-treated cells were performed to investigate its functions on global. replication factor C subunit 4 (RFC4) was identified as a potential binding target of PD by thermal proteome profiling and their binding sites were further exposed by peptide-centric local stability assay. PD-RFC4 complex promotes the degradation of Notch1 and Notch3 by reducing nuclear entry of their domains. Compared with control treatment, the differentially expressed proteins induced by PD were found to be primarily involved in ferroptosis, ubiquitination, platinum drug resistance, and ribosome-related processes. The ubiquitin proteome analysis revealed that proteins associated with the Notch pathway underwent ubiquitin modifications. PD binds to RFC4 and inhibits its activity, leading to downregulation of the Notch signaling pathway, ultimately triggering cancer cell apoptosis. PD is a natural product with potential therapeutic value for NSCLC.

Saponins↗

PubMed2026

Development and preclinical evaluation of a decoy DLL4-encoding oncolytic HSV-1 for high-grade glioma.

Preclinical and clinical investigation of oncolytic HSV-1 (oHSV) treatment for cancer has indicated increased Notch signaling in tumors after treatment. Since Notch activation often heralds cancer cell stemness, angiogenesis, and invasion, the induction of this pathway after oHSV virotherapy can support tumor growth and limit response to virotherapy. Here, we evaluated the impact of blocking DLL4, a Notch ligand, on virotherapy. Matched tumor biopsies pre- and post-oHSV (CAN-3110, NCT03152318) treatment revealed an induction of DLL4 post-therapy. We observed that expression of a recombinant soluble decoy DLL4 (sDLL4) could block Notch activation in tumor cells. Thus, we engineered an oHSV vector designed to encode soluble DLL4 (OVsDLL4) to block ligand-mediated Notch signaling. RNA sequencing and gene set enrichment analysis revealed that, relative to control oHSV, OVsDLL4 blocked Notch and sprouting angiogenesis pathways after treatment. Despite slower virus replication in vitro, OVsDLL4 cytotoxicity remained effective against tumor cells. Transcriptome profiling also indicated a significant dysregulation of metabolic pathways related to oxidative phosphorylation and glutathione metabolism, in accordance with increased oxygen consumption observed by Seahorse analysis in cells expressing sDLL4. OVsDLL4-treated cells further showed increased reactive oxygen species relative to control oHSV-treated cells. Co-culture of infected tumor cells with immune cells revealed that OVsDLL4 treatment polarized them toward an inflammatory phenotype. In vivo, the therapeutic efficacy of OVsDLL4 was underscored, as treatment of glioma-bearing mice resulted in reduced tumor burden and prolonged survival.

Journal Article↗

PubMed2026

Colitogenic Environment Suppresses Notch/Mechanistic Target of Rapamycin-Mediated Epithelial Proliferation to Promote Goblet Cell Differentiation in the Colon.

Epithelial barrier dysfunction is a hallmark of inflammatory bowel diseases; however, the mechanisms underlying such impairment remain incompletely understood. In the present study, a dextran sulfate sodium-induced colitis model was used to investigate how the inflammatory environment damages the intestinal mucosa. The results demonstrated that colitogenic ambiance enhances intestinal epithelial cell death, delays epithelial cell proliferation, and exacerbates mucosal erosion. Unexpectedly, this work identified a previously unrecognized role for Notch signaling in mediating these effects. Specifically, the colitogenic milieu reduces Notch/mechanistic target of rapamycin complex 1 (mTORC1)-mediated intestinal epithelial cell proliferation to promote goblet cell differentiation. Chemical activation of Notch signaling stimulated intestinal epithelial cell proliferation and reduced goblet cell differentiation in the colitic mucosa, further aggravating mucosal damage. Conversely, inhibition of Notch or mTORC1 signaling during mucosal repair reduced intestinal epithelial cell proliferation and enhanced goblet cell differentiation, corroborating the implication of Notch and mTORC1 signaling in both processes. Collectively, these findings uncover a context-dependent role for the Notch-mechanistic target of rapamycin axis in regulating intestinal epithelial cell proliferation and differentiation in the colitic mucosa and suggest that its targeted modulation may hold therapeutic potential in inflammatory bowel diseases.

Animals↗

PubMed2024

Androgen Effects on Alcohol-induced Liver Fibrosis Are Controlled by a Notch-dependent Epigenetic Switch.

BACKGROUND & AIMS: Alcohol-associated liver disease (ALD) is a major cause of alcohol-related mortality. Sex is an important variable; however, the mechanism behind sex differences is not yet established. METHODS: Kdm5b flox/flox Kdm5c flox male mice were subjected to gonadectomy or sham surgery. Mice were fed a Western diet and 20% alcohol in the drinking water for 18 weeks. To induce knockout, mice received 2 × 1011 genome copies of AAV8-CMV-Cre or AAV8-control. To test the role of Notch, mice were treated with 10 mg/kg of avagacestat for 4 weeks. RESULTS: We found that Kdm5b/Kdm5c knockout promoted alcohol-induced liver disease, whereas gonadectomy abolished this effect, suggesting that male sex hormones promote liver disease in the absence of KDM5 demethylases. In contrast, in the thioacetamide-induced fibrosis model, male sex hormones showed a protective effect regardless of genotype. In human liver disease samples, we found that androgen receptor expression positively correlated with fibrosis levels when KDM5B levels were low and negatively when KDM5B was high, suggesting that a KDM5B-dependent epigenetic state defines the androgen receptor role in liver fibrosis. Using isolated cells, we found that this difference was due to the differential effect of testosterone on hepatic stellate cell activation in the absence or presence of KDM5B/KDM5C. Moreover, this effect was mediated by KDM5-dependent suppression of Notch signaling. In KDM5-deficient mice, Notch3 and Jag1 gene expression was induced, facilitating testosterone-mediated induction of Notch signaling and stellate cell activation. Inhibiting Notch with avagacestat greatly reduced liver fibrosis and abolished the effect of Kdm5b/Kdm5c loss. CONCLUSIONS: Male sex hormone signaling can promote or prevent alcohol-associated liver fibrosis depending on the KDM5-dependent epigenetic state.

Animals↗

PubMed2026

Oncolytic HSV-1-Mediated JAG1 Blockade Induces Glioma Senescence-Associated Secretory Phenotype to Increase Macrophage Activation and Cetuximab-Mediated Senolysis.

UNLABELLED: Oncolytic HSV-1 (oHSV) treatment induces Notch signaling and myelosuppression in the tumor microenvironment (TME) of preclinical cancer models. Clinically, the Notch ligand JAG1 was upregulated in patients with recurrent high-grade glioma treated with the oHSV CAN-3110 and correlated with poor prognosis. To better understand endogenous JAG1-mediated signaling in glioma cells and tumor-associated macrophages (TAM), we engineered a JAG1-antagonizing oHSV (OD-0J1) and interrogated its impact on cancer and myeloid cells in the TME. OD-0J1 antagonized JAG1-mediated Notch signaling and suppressed tumor growth in athymic nude and humanized mice, an effect reliant on Notch signaling in tumor cells. Kinome profiling revealed that OD-0J1 treatment suppressed CDK1, resulting in activation of the G2-M cell cycle checkpoint. Cell cycle arrest led to senescence and correlated with increased reactive oxygen species, p62, and autophagosome accumulation and senescence-associated β-galactosidase activity. OD-0J1-induced senescence resulted in increased production of inflammatory chemokines and damage-associated molecular patterns (DAMP), such as IL1β, HMGB1, and extracellular ATP. Coculturing macrophages with OD-0J1-infected tumor cells led to stimulation of chemotactic and proinflammatory pathways, as well as increased Fc receptor activation. Single-cell RNA sequencing and flow cytometric analysis of F4/80+ cells isolated from tumors showed a shift from tumor-supporting TAMs to inflammatory macrophages upon OD-0J1 treatment. Heightened EGFR activation in senescent cells was a mechanism to escape cell death, which created a unique opportunity for cetuximab as a senolytic agent. Combination therapy reduced EGFR signaling and induced macrophage-mediated antibody-dependent cellular cytotoxicity, thereby increasing the antitumor therapeutic efficacy of OD-0J1. SIGNIFICANCE: Leveraging JAG1 antagonism in the context of oncolytic virotherapy rewires macrophage polarization within the tumor microenvironment, which has wide implications for sensitizing tumors to antibodies, senolytic agents, and BiTE therapies.

Humans↗

PubMed2026

Optimizing NGN2 Dosage Enhances the Neuronal Enrichment of iPSC-Derived Neuronal Cultures.

Proteomic analysis of highly neuron-enriched iPSC-derived cultures can provide valuable insights into the pathogenesis of neurological disease by minimizing confounding signals from non-neuronal populations. However, single-cell iPSC clones with stable NGN2 integration at the AAVS1 locus exhibit spontaneous loss of the mCherry reporter. In addition, following NGN2 induction, cultures frequently contain proliferative progenitor cells that compromise neuronal physical integrity. Here, we show that increased DNA methylation of the EF1-α promoter is associated with mCherry silencing. Importantly, reporter silencing does not affect iNeuron derivation, as evidenced by two lines of evidence. First, single-cell proteomic analysis indicated that mCherry silencing does not drive detectable proteomic divergence in undifferentiated iPSCs. Second, bulk proteomics and immunofluorescence analyses indicated that iPSC-derived neuronal cultures, whether expressing or lacking mCherry, resemble cortical glutamatergic neurons. Instead, the primary confounding factor in iNeuron generation was suboptimal neuronal conversion, which led to cell aggregates comprised of actively proliferating progenitor cells and astrocytes as the culture developed. We found that a 4-day period of NGN2 induction substantially increases neuronal maturation and the expression of neuronal-specific markers. Moreover, transient inhibition of Notch signaling is consistent with a reduction in progenitor cells. Finally, we observed that monoallelic NGN2 integration, rather than biallelic integration, preferentially increases expression of the CNS neuronal marker GPM6A over PNS markers (PRPH, POU4F1, ILS1).

Basic Helix-Loop-Helix Proteins↗

PubMed2026

OscillomeR infers ultradian oscillations and targets of the Hes family.

The Hes family, basic-helix-loop-helix transcription factors and downstream effectors of Notch signaling, regulate the fate choices of pancreatic progenitors, muscle stem cells, neuronal progenitors, and presomitic mesoderm cells. Bioluminescence imaging (BLI) has revealed ultradian oscillatory dynamics of Hes-family members Hes1, Hes5, and Hes7. However, identifying which of the Hes target genes also oscillate remains challenging due to the time-consuming and costly nature of tracking individual target genes using BLI. Here, we propose OscillomeR, a computational framework that reconstructs ultradian oscillations from RNA-sequencing data to identify oscillatory target genes at high throughput. OscillomeR predicts thousands of oscillatory genes in synchronized or unsynchronized cell types, identifying both known and novel Hes-family targets. It also captures the dynamic rewiring of gene-regulatory networks during cell differentiation. Overall, OscillomeR is an effective tool for elucidating the functions of oscillatory transcription factors at the genomic scale.

Hes family↗

PubMed2026

The DLX/Notch axis is necessary for spatiotemporal regulation of neural cell fate.

Neuronal-glial cell fate switch during forebrain development is highly regulated. DLX transcription factors are necessary for promoting GABAergic interneuron differentiation and migration but the mechanisms for concomitant repression of glial fate in neural progenitors remain elusive. Here, the DLX2 regulatory network dynamic in the developing ventral telencephalon is characterised using a multi-omic approach at single-cell resolution, including single-cell whole genome spatial transcriptomics. We identify a secondary proliferative zone in the ventral subventricular zone and spatiotemporal-context dependent Notch pathway repression by DLX2 in maintaining progenitor populations and facilitating neural differentiation. We find that DLX2 controls cell fate determination by directly repressing Notch signalling genes as well as glial fate-promoting transcription factors, thereby inhibiting early adoption of oligodendroglial differentiation during neurogenesis. Here, we show that temporal cell fate switch is mediated by DLX2 via a multilayer gene regulatory network, redefining current understanding of neuronal-glial cell specification mechanisms in the developing telencephalon.

Animals↗

PubMed2026

Genome-wide cis-expression Quantitative Trait Loci (eQTL) and transcriptomic signals reveal distinct molecular regulation across correlated feed efficiency traits.

INTRODUCTION: Feed efficiency (FE) is a complex trait which determines livestock production profitability, yet the molecular mechanisms behind it remain unclear. This study investigated the blood transcriptomic profile of lambs, alongside genotype data with the aim to uncover the genetic basis of FE traits such as absolute dry matter intake (DMIabsolute), DMI adjusted for body size (DMIadjusted), average daily live weight gain (ADG), and residual feed intake (RFI). MATERIALS AND METHODS: Bulk RNA-Seq and genotype data were analysed using three complementary approaches: differential gene expression (DGE) analysis, weighted gene co-expression network analysis (WGCNA), and cis-expression Quantitative Trait Loci (cis-eQTL) mapping. These methods were used independently to identify genes and regulatory networks associated with FE traits and to investigate evidence supporting multi-trait candidate gene selection. RESULTS: DGE analysis revealed 2, 24, 85 and 4 differentially expressed genes for DMIabsolute, DMIadjusted, ADG, and RFI (Padjusted < 0.05), functionally enriched in sensory perception, ATP-dependent chromatin remodeling, Notch signaling and immune response pathways. 9 gene modules significantly associated with the FE traits (P ≤ 0.05) with correlations ranging from r = -0.56 to 0.49, were identified using WGCNA. Single nucleotide polymorphism (SNP)-level cis-eQTL analysis identified 93 eSNPs associated with 74 genes (false discovery rate (FDR) < 0.05), while permutation-derived gene level analysis identified 280 eGenes (FDR < 0.2, empirical P < 0.03). Across the three analyses, applying thresholds of DGE (Padjusted < 0.05), WGCNA (correlation, P ≤ 0.05), and cis-eQTL gene-level significance (empirical P < 0.05), multiple overlapping genes were identified including DNMT3A, KANSL1, NCOR1 for DMIadjusted, ACOX2, FANCF, CIMIP2B, LOC101115106, ARMH2, LOC132657496 for ADG, and LOC114114576 for RFI representing regulators of variations in FE. DISCUSSION: The integration of DGE, WGCNA, and cis-eQTL analyses identified key genes and regulatory mechanisms associated with variation in FE traits. These results highlight that integrated multi-trait candidate gene identification approaches can reveal key genes that lower feed intake while maintaining animal growth, supporting breeding strategies aimed at improving efficiency and long-term economic sustainability in sheep.

average daily gain (ADG)↗

PubMed2026

Rbp-Jκ controls NK cell late maturation and migration via chromatin landscape remodeling.

The transcriptional regulator Rbp-Jκ is a pivotal molecular switch in Notch signaling; however, its cell-intrinsic role in natural killer (NK) cell maturation and migration remains incompletely understood. Here, we demonstrate that NK cell-specific deletion of Rbp-Jκ (Ncr1iCre × Rbp-Jκfl/fl, Rbp-JκΔNK) impairs NK cell terminal maturation and migration, as evidenced by increased retention of NK cells in bone marrow, a reduced number of circulating NK cells and decreased expression of migration mediators (CD62L, S1pr5, and Cx3cr1). Despite exhibiting an activated phenotype, Rbp-Jκ-deficient NK cells fail to control B16F10 lung metastases in vivo because of impaired tissue mobilization. Multiomics (scRNA-seq/scATAC-seq, bulk ATAC-seq, and CUT&Tag) reveal that Rbp-Jκ orchestrates chromatin remodeling in NK cells, suppressing the expression of genes related to NK cell activation and cytotoxicity while promoting the expression of genes involved in ribosome and oxidative phosphorylation. Notably, Rbp-Jκ directly binds to the Kruppel-like factor 2 (Klf2) promoter, and loss of Rbp-Jκ reduces both the mRNA and protein levels of Klf2. Klf2 overexpression rescues the decreased expression of CD62L and CX3CR1 in Rbp-Jκ-deficient NK cells. The cooccupancy of Rbp-Jκ and Klf2 at shared genomic loci is confirmed by ChIP-qPCR. In summary, our study reveals that Rbp-Jκ acts as a master regulator of NK cell terminal maturation and tissue homing via chromatin reprogramming, with Klf2 acting as its critical downstream transcription factor.

Animals↗

PubMed2024

Genomic landscape of hepatocellular carcinoma in Egyptian patients by whole exome sequencing.

BACKGROUND: Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Chronic hepatitis and liver cirrhosis lead to accumulation of genetic alterations driving HCC pathogenesis. This study is designed to explore genomic landscape of HCC in Egyptian patients by whole exome sequencing. METHODS: Whole exome sequencing using Ion Torrent was done on 13 HCC patients, who underwent surgical intervention (7 patients underwent living donor liver transplantation (LDLT) and 6 patients had surgical resection}. RESULTS: Mutational signature was mostly S1, S5, S6, and S12 in HCC. Analysis of highly mutated genes in both HCC and Non-HCC revealed the presence of highly mutated genes in HCC (AHNAK2, MUC6, MUC16, TTN, ZNF17, FLG, MUC12, OBSCN, PDE4DIP, MUC5b, and HYDIN). Among the 26 significantly mutated HCC genes-identified across 10 genome sequencing studies-in addition to TCGA, APOB and RP1L1 showed the highest number of mutations in both HCC and Non-HCC tissues. Tier 1, Tier 2 variants in TCGA SMGs in HCC and Non-HCC (TP53, PIK3CA, CDKN2A, and BAP1). Cancer Genome Landscape analysis revealed Tier 1 and Tier 2 variants in HCC (MSH2) and in Non-HCC (KMT2D and ATM). For KEGG analysis, the significantly annotated clusters in HCC were Notch signaling, Wnt signaling, PI3K-AKT pathway, Hippo signaling, Apelin signaling, Hedgehog (Hh) signaling, and MAPK signaling, in addition to ECM-receptor interaction, focal adhesion, and calcium signaling. Tier 1 and Tier 2 variants KIT, KMT2D, NOTCH1, KMT2C, PIK3CA, KIT, SMARCA4, ATM, PTEN, MSH2, and PTCH1 were low frequency variants in both HCC and Non-HCC. CONCLUSION: Our results are in accordance with previous studies in HCC regarding highly mutated genes, TCGA and specifically enriched pathways in HCC. Analysis for clinical interpretation of variants revealed the presence of Tier 1 and Tier 2 variants that represent potential clinically actionable targets. The use of sequencing techniques to detect structural variants and novel techniques as single cell sequencing together with multiomics transcriptomics, metagenomics will integrate the molecular pathogenesis of HCC in Egyptian patients.

Humans↗

PubMed2025

A case of congenital heart defects and familial exudative vitreoretinopathy caused by activation of a cryptic splice donor in NOTCH1.

BACKGROUND: NOTCH1 is associated with two disorders of vascular development, Adams-Oliver Syndrome 5 (AOS5) and aortic valve disease 1 (AOVD1). Here we report a disease-causing variant in NOTCH1 that has a previously undemonstrated effect on splicing. Additionally, we found that the proband has the optic phenotype of familial exudative vitreoretinopathy (FEVR) which has been reported for probands with pathogenic variants in genes in the notch signaling pathway, but never for NOTCH1. CASE PRESENTATION: The proband presented with a ventricular septal defect, pulmonic stenosis, and ocular findings consistent with familial exudative vitreoretinopathy (FEVR), which NOTCH1 has not been associated with to date. Trio exome sequencing identified a paternally inherited variant of uncertain significance in NOTCH1:c.2153 A > G. We assessed the variant's effect using RT-PCR, finding an increased use of a cryptic donor compared to the control. On this basis, we were able to re-classify this variant as pathogenic. CONCLUSIONS: We expand the phenotypic spectrum of NOTCH1 and contribute to the building evidence that variants in NOTCH1 cause a spectrum of disorders of vascular development.

Humans↗

PubMed2025

Genetic insight into lung neuroendocrine tumors: Notch and Wnt signaling pathways as potential targets.

BACKGROUND: The molecular landscape of lung neuroendocrine neoplasms is still poorly characterized, making it difficult to develop a molecular classification and personalized therapeutic approaches. Significant clinical heterogeneity of these malignancies has been highlighted among poorly differentiated histotypes and within the subgroup of well-differentiated neuroendocrine tumors (NET). Currently, the main prognostic factors of lung NET include stage, histotype, grade, peripheral location, and demographic parameters. To gain deeper insights into the genomic underpinnings of lung NETs, we conducted a pilot investigation to uncover potential genetic mutations and copy number variations (CNVs) implicated in their pathogenesis. METHODS: Formalin-fixed, paraffin-embedded intraoperative tumor biopsies and matched peripheral blood mononuclear cell samples were collected from six consecutive patients with lung NETs. The whole exome sequencing (WES) was performed to profile germline and somatic mutations, identify novel genetic alterations, and detect CNVs. Clinical and pathological data were systematically documented at diagnosis and during follow-up. RESULTS: The WES analysis identified a subset of mutations shared between germline and somatic; some were of particular clinical interest as they were associated with tumor proliferation and potential therapeutic targets such as the genes KDM5C, ATR, COL7A1, NOTCH4, PTPRS, SMO, SPEN, SPTA1, TAF1. These mutations were predominantly linked to chromatin remodeling and were involved in critical oncogenic pathways such as Notch and Wnt signaling. CONCLUSIONS: This pilot study highlights the potential role of NGS analysis on solid biopsy in the assessment of the mutational profile of lung NET. A comparison of germline and somatic mutations is critical to identifying putative tumor driver mutations. In perspective, the enrichment of a subpopulation of cancer cells in the blood, with one or more specific mutations, is information of enormous clinical relevance, either for prognosis or therapeutic decisions. Translational studies on large prospective series are required to establish the role of liquid biopsy in lung NET.

Humans↗

PubMed2025

Notch pathway defines an aggressive and immune-suppressive phenotype associated with checkpoint inhibitor resistance in pan-gastrointestinal adenocarcinomas.

The Notch pathway regulates the homeostasis and tumorigenesis of gastrointestinal epithelium. Given its roles in cancer stem cell capacity and cancer immunity, we hypothesized that Notch activation can predict poor prognosis and resistance to immune checkpoint inhibitors (ICIs) in gastrointestinal adenocarcinoma (GIAC). The mRNA expression and genomic alterations of Notch pathway were characterized in esophagus (ESAD), stomach (STAD), colon (COAD), or rectum (READ) adenocarcinomas from The Cancer Genome Atlas (TCGA) dataset. The prognostic model (mRNA-score) was constructed using the TCGA dataset (the training set) and was validated in 3 independent sets (GSE19417 [ESAD], GSE84437 [STAD], and GSE40967 [COAD]). The associations of the mRNA-score with drug sensitivity, immune cell infiltration, and immunotherapy efficacy were, respectively, analyzed using the Genomics of Drug Sensitivity in Cancer (GDSC) database, the TCGA dataset, and multiple clinical cohorts including GSE165252, PRJEB25780, IMvigor210, and CheckMate-009/010/025. Notch pathway genes exhibited conserved genomic/transcriptomic features across four GIAC subtypes. Three pan-GIAC clusters were determined by unsupervised clustering, and the cluster with higher expression of the Notch pathway genes had shorter overall survival (OS), immunosuppressive microenvironment, and higher scores of the signatures concerning angiogenesis, cell cycle, PI3K-AKT-mTOR, TGF-β, glycolysis, etc. A prognostic algorithm (mRNA-score) was constructed, which was correlated with poor OS in the training set (TCGA, P < 0.001) and three validation sets (GSE19417, P = 0.025; GSE84437, P = 0.001, GSE40967, P = 0.007). A high mRNA-score was linked with more "resting"/ "anti-inflammatory" rather than "activated"/ "pro-inflammatory" tumor-infiltrating immune cells and ICI resistance in GIACs (GSE165252, P = 0.047; PRJEB25780, P = 0.047) and other solid tumors such as urothelial carcinoma and clear cell renal cell carcinoma. Our findings demonstrate the utility of the Notch pathway in predicting prognosis and ICI resistance. Further studies are warranted to explore the efficacy of Notch inhibitors as immunotherapeutic adjuvants to overcome ICI resistance.

Humans↗