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Results for “DLL4”

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PubMed2026

Endothelial PERK restricts lymphoid regeneration by reducing DLL4-NOTCH3 signaling at the Pre-B niche.

Delayed immune recovery after hematopoietic stem cell (HSC) transplantation is associated with a poor clinical outcome. We study the role of unfolded protein response (ER stress) in hematopoietic regeneration within the bone marrow (BM) microenvironment. We reveal that BM endothelium PERK activation is a prominent feature of patients with leukemia and is a hallmark response in mice following ionizing irradiation. Ablating endothelial Perk boosts NOTCH ligand DLL4 expression and promotes DLL4-dependent early HSC and B progenitor regeneration. Single-cell analysis reveals that endothelial DLL4 activates NOTCH3 expressed by mesenchymal stroma cells, and that the PERK-DLL4 axis coordinates the regulation of lymphoid commitment. NOTCH3 is critical for the upregulation of IL7 following irradiation and the expansion of lymphoid progenitors. These findings not only unveil an ER stress-controlled vascular-stroma signaling mechanism in regenerative hematopoiesis but also highlight PERK blockade as a promising strategy to improve immune recovery after myeloablative transplantation.

CP: cell biology↗

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↗

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↗