更新于：2024-11-01

DLL1

更新于：2024-11-01

基本信息

别名

delta like canonical Notch ligand 1、Delta-like protein 1、Delta1

+ [3]

简介

Transmembrane ligand protein of NOTCH1, NOTCH2 and NOTCH3 receptors that binds the extracellular domain (ECD) of Notch receptor in a cis and trans fashion manner (PubMed:11006133). Following transinteraction, ligand cells produce mechanical force that depends of a clathrin-mediated endocytosis, requiring ligand ubiquitination, EPN1 interaction, and actin polymerisation; these events promote Notch receptor extracellular domain (NECD) transendocytosis and triggers Notch signaling through induction of cleavage, hyperphosphorylation, and nuclear accumulation of the intracellular domain of Notch receptors (NICD) (By similarity). Is required for embryonic development and maintenance of adult stem cells in many different tissues and immune systeme; the DLL1-induced Notch signaling is mediated through an intercellular communication that regulates cell lineage, cell specification, cell patterning and morphogenesis through effects on differentiation and proliferation (PubMed:11581320). Plays a role in brain development at different level, namely by regulating neuronal differentiation of neural precursor cells via cell-cell interaction, most likely through the lateral inhibitory system in an endogenous level dependent-manner. During neocortex development, Dll1-Notch signaling transmission is mediated by dynamic interactions between intermediate neurogenic progenitors and radial glia; the cell-cell interactions are mediated via dynamic and transient elongation processes, likely to reactivate/maintain Notch activity in neighboring progenitors, and coordinate progenitor cell division and differentiation across radial and zonal boundaries. During cerebellar development, regulates Bergmann glial monolayer formation and its morphological maturation through a Notch signaling pathway. At the retina and spinal cord level, regulates neurogenesis by preventing the premature differentiation of neural progenitors and also by maintaining progenitors in spinal cord through Notch signaling pathway. Also controls neurogenesis of the neural tube in a progenitor domain-specific fashion along the dorsoventral axis. Maintains quiescence of neural stem cells and plays a role as a fate determinant that segregates asymmetrically to one daughter cell during neural stem cells mitosis, resulting in neuronal differentiation in Dll1-inheriting cell. Plays a role in immune systeme development, namely the development of all T-cells and marginal zone (MZ) B-cells (By similarity). Blocks the differentiation of progenitor cells into the B-cell lineage while promoting the emergence of a population of cells with the characteristics of a T-cell/NK-cell precursor (PubMed:11581320). Also plays a role during muscle development. During early development, inhibits myoblasts differentiation from the medial dermomyotomal lip and later regulates progenitor cell differentiation. Directly modulates cell adhesion and basal lamina formation in satellite cells through Notch signaling. Maintains myogenic progenitors pool by suppressing differentiation through down-regulation of MYOD1 and is required for satellite cell homing and PAX7 expression. During craniofacial and trunk myogenesis suppresses differentiation of cranial mesoderm-derived and somite-derived muscle via MYOD1 regulation but in cranial mesoderm-derived progenitors, is neither required for satellite cell homing nor for PAX7 expression. Also plays a role during pancreatic cell development. During type B pancreatic cell development, may be involved in the initiation of proximodistal patterning in the early pancreatic epithelium. Stimulates multipotent pancreatic progenitor cells proliferation and pancreatic growth by maintaining HES1 expression and PTF1A protein levels. During fetal stages of development, is required to maintain arterial identity and the responsiveness of arterial endothelial cells for VEGFA through regulation of KDR activation and NRP1 expression. Controls sprouting angiogenesis and subsequent vertical branch formation througth regulation on tip cell differentiation. Negatively regulates goblet cell differentiation in intestine and controls secretory fat commitment through lateral inhibition in small intestine. Plays a role during inner ear development; negatively regulates auditory hair cell differentiation. Plays a role during nephron development through Notch signaling pathway. Regulates growth, blood pressure and energy homeostasis (By similarity).

关联

项与 DLL1 相关的药物

Dl1.72

靶点

DLL1

作用机制

DLL1 inhibitors

在研机构

Instituto de Biologia Experimental e Tecnológica

原研机构

Instituto de Biologia Experimental e Tecnológica

在研适应症

HR阳性乳腺癌

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

NOV-110101

靶点

DLL1

作用机制

DLL1 modulators

在研机构-

原研机构

National OncoVenture

在研适应症-

非在研适应症

肝癌 [+1]

最高研发阶段无进展

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 DLL1 相关的临床结果

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100 项与 DLL1 相关的转化医学

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0 项与 DLL1 相关的专利（医药）

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764

项与 DLL1 相关的文献（医药）

2024-11-01·Breast Cancer Research and Treatment

CD133 expression is associated with less DNA repair, better response to chemotherapy and survival in ER-positive/HER2-negative breast cancer

Article

作者: Roy, Arya Mariam ; Oshi, Masanori ; Takabe, Kazuaki ; Endo, Itaru ; Huang, Jing Li ; Sato, Takumi ; Chida, Kohei

PURPOSECD133, a cancer stem cells (CSC) marker, has been reported to be associated with treatment resistance and worse survival in triple-negative breast cancer (BC). However, the clinical relevance of CD133 expression in ER-positive/HER2-negative (ER + /HER2-) BC, the most abundant subtype, remains unknown.METHODSThe BC cohorts from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC, n = 1904) and The Cancer Genome Atlas (TCGA, n = 1065) were used to obtain biological variables and gene expression data.RESULTSEpithelial cells were the exclusive source of CD133 gene expression in a bulk BC. CD133-high ER + /HER2- BC was associated with CD24, NOTCH1, DLL1, and ALDH1A1 gene expressions, as well as with WNT/β-Catenin, Hedgehog, and Notch signaling pathways, all characteristic for CSC. Consistent with a CSC phenotype, CD133-low BC was enriched with gene sets related to cell proliferation, such as G2M Checkpoint, MYC Targets V1, E2F Targets, and Ki67 gene expression. CD133-low BC was also linked with enrichment of genes related to DNA repair, such as BRCA1, E2F1, E2F4, CDK1/2. On the other hand, CD133-high tumors had proinflammatory microenvironment, higher activity of immune cells, and higher expression of genes related to inflammation and immune response. Finally, CD133-high tumors had better pathological complete response after neoadjuvant chemotherapy in GSE25066 cohort and better disease-free survival and overall survival in both TCGA and METABRIC cohorts.CONCLUSIONCD133-high ER + /HER2- BC was associated with CSC phenotype such as less cell proliferation and DNA repair, but also with enhanced inflammation, better response to neoadjuvant chemotherapy and better prognosis.

2024-10-01·Cancer Cell

A proteogenomic surfaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma

Article

作者: Conkrite, Karina L ; Pawel, Bruce ; Maris, John M ; Havenith, Karin E. ; Zhong, Chuwei ; Smith, Malcolm A ; Bosse, Kristopher R. ; Bhatti, Tricia ; Maris, John M. ; Glisovic-Aplenc, Tina ; Earley, Eric J ; van Berkel, Patrick H. ; Mosse, Yael P ; Smith, Malcolm A. ; Miller, Daniel P ; Zammarchi, Francesca ; Teicher, Beverly ; Hartnett, Nicholas ; Rathi, Komal S ; Patel, Khushbu ; Modi, Apexa ; Sorensen, Poul H. ; Diskin, Sharon J ; Lane, Maria V ; Conkrite, Karina L. ; Mosse, Yael P. ; Sidoli, Simone ; Pogoriler, Jennifer ; Rokita, Jo Lynne ; Rathi, Komal S. ; Ennis, Brian ; Raman, Pichai ; Tsang, Matthew ; Garcia, Benjamin A ; Krytska, Kateryna ; Brown, Miguel A. ; Erickson, Stephen W. ; Lopez, Raphael D ; Lopez, Raphael D. ; Miller, Daniel P. ; Delaidelli, Alberto ; Earley, Eric J. ; Radaoui, Alexander B ; Sorensen, Poul H ; Hamilton, Amber K. ; Hamilton, Amber K ; van Berkel, Patrick H ; Havenith, Karin E ; Lane, Maria V. ; Garcia, Benjamin A. ; Erickson, Stephen W ; Diskin, Sharon J. ; Zhang, Bo ; Brown, Miguel A ; Bosse, Kristopher R ; Martinez, Daniel ; Radaoui, Alexander B.

Cancer immunotherapies produce remarkable results in B cell malignancies; however, optimal cell surface targets for many solid cancers remain elusive. Here, we present an integrative proteomic, transcriptomic, and epigenomic analysis of tumor and normal tissues to identify biologically relevant cell surface immunotherapeutic targets for neuroblastoma, an often-fatal childhood cancer. Proteogenomic analyses reveal sixty high-confidence candidate immunotherapeutic targets, and we prioritize delta-like canonical notch ligand 1 (DLK1) for further study. High expression of DLK1 directly correlates with a super-enhancer. Immunofluorescence, flow cytometry, and immunohistochemistry show robust cell surface expression of DLK1. Short hairpin RNA mediated silencing of DLK1 in neuroblastoma cells results in increased cellular differentiation. ADCT-701, a DLK1-targeting antibody-drug conjugate (ADC), shows potent and specific cytotoxicity in DLK1-expressing neuroblastoma xenograft models. Since high DLK1 expression is found in several adult and pediatric cancers, our study demonstrates the utility of a proteogenomic approach and credentials DLK1 as an immunotherapeutic target.

2024-10-01·ELECTROPHORESIS

A semen‐specific deoxyribonucleic acid methylation model for epigenetic age estimation and its robustness under environmental challenges

Article

作者: Filoglu, Gonul ; Ersoy, Gokhan ; Er, Sena ; Abik, Zehra ; Ozkara, Hamdi ; Bulbul, Ozlem

AbstractIn forensic investigations, semen samples are a common form of biological evidence, especially in cases involving sexual assault. Therefore, accurately estimating the age of an individual is crucial in criminal cases. This study presents a novel age estimation model based on semen‐specific CpG methylation patterns. A multiplex panel was developed, consisting of 12 CpG sites (PARP14, C5orf25, cg23488376, MXRA5, PFKFB3, DLL1, NOX4, cg12837463, TTC7B, KCNA7, NKX2‐1, and SYNE4), which exhibit strong correlations with age. Additionally, this study investigates the resilience of these methylation markers under simulated environmental challenges. We collected ejaculate samples from a diverse cohort of 115 male individuals, aged 20–71 years, who underwent deoxyribonucleic acid extraction and bisulfite conversion. Methylation levels of the selected CpG sites were assessed using a SNaPshot assay, which revealed significant correlations with chronological age. We developed and validated two robust age estimation models through stepwise and enter regression analyses, achieving reliable accuracy with mean absolute errors ranging from 3.81 to 4.1 years. Additionally, the study also investigated the robustness of semen stains under diverse environmental conditions, including fabric type, washing, hematin exposure, and UV‐C light. The selected methylation markers demonstrated remarkable resilience despite the challenges posed by washing procedures and environmental exposure, confirming their potential for age estimation in forensic genetics. This research presents successful age estimation models, emphasizing the strong correlations between methylation levels and chronological age. The proposed methodology's accuracy is affirmed through model validation on an independent test set, while also highlighting the resilience of semen stains on fabrics under varying storage and washing conditions.

项与 DLL1 相关的新闻（医药）

2024-10-24

·PRNewswire

Children's Hospital of Philadelphia Researchers Find Promising New Immunotherapy Target in Neuroblastoma and Other Cancers

Study offers hope for treating a potentially deadly childhood cancer PHILADELPHIA, Oct. 24, 2024 /PRNewswire/ -- Researchers at Children's Hospital of Philadelphia (CHOP) announced significant findings in the treatment of neuroblastoma, a cancer of the peripheral nervous system that usually occurs as a solid tumor in a child's chest or abdomen. The study offers insights that could lead to new, personalized medicine approaches in immunotherapy treatment. The findings were published today in the journal Cancer Cell. Neuroblastoma is the most common cancer in infants, accounting for a disproportionate share of pediatric cancer deaths. Currently, monoclonal antibody-based immunotherapy is the only Food and Drug Administration (FDA) approved treatment for neuroblastoma. However, this type of immunotherapy can cause painful side effects, and patients often relapse. All these factors led researchers to seek new and innovative approaches to treating this disease and safely improve cure rates. In this study, researchers used a multi-omics approach to analyze and identify potential new targets for immunotherapy, integrating proteomic, transcriptomic, and epigenomic data to pinpoint biologically relevant proteins on the surfaces of cancer cells that are visible to the immune system. Reviewing comprehensive data helps scientists understand how cells function and what goes wrong in diseases like cancer. Based on their findings, the researchers prioritized the protein, Delta-like canonical notch ligand 1 (DLK1). They showed that high expression of DLK1 in cancer cells promotes tumor growth and discovered how neuroblastoma cells increase DLK1 levels. They also found that DLK1 is produced at a higher rate in many childhood and adult cancers. "Our study demonstrates the power of an integrative multi-omics approach to identify immunotherapeutic targets," said senior author, Sharon J. Diskin, PhD, a member of the Center for Childhood Cancer Research and Department of Biomedical and Health Informatics at CHOP and an Associate Professor of Pediatrics in the Perelman School of Medicine at the University of Pennsylvania. The researchers subsequently studied a novel treatment called ADCT-701, an antibody-drug conjugate (ADC) that delivers a potent therapy targeting DLK1-expressing cancer cells, as part of the National Cancer Institute's (NCI) Pediatric Preclinical in Vivo Testing (PIVOT) Program. They demonstrated that ADCT-701 was highly effective in eradicating highly resistant patient-derived tumors. The NCI is currently conducting a phase 1 clinical trial for treatment of neuroendocrine neoplasms with ADCT-701 in adults 18 and older. "Our findings provided important validation and preclinical data to support an ongoing first-in-human DLK1-directed immunotherapy clinical trial for adult patients diagnosed with neuroendocrine neoplasms, including neuroblastoma," said the study's primary author, Amber Hamilton, PhD, a post-doctoral fellow at CHOP. "This research brings hope to families, offering the potential for more effective treatments." The research was supported by a grant from the W.W. Smith Charitable Trust, an Innovation Award from Alex's Lemonade Stand Foundation, and a Stand Up 2 Cancer-St. Baldrick's Pediatric Dream Team Translational Research Grant (SU2C-AACR-DT1113 ). This work was also supported by National Institutes of Health (NIH) grants U54-CA232568, R01-CA204974, R01-CA237562, R03-CA230366, U01-CA199287, R35-CA220500, U01-CA263957, U01-CA199222, F31-CA225069 and T32-CA009140. The work was delivered in part by the NexTGen Cancer Grand Challenges partnership funded by Cancer Research UK (CGCATF-2021/100002), the National Cancer Institute (CA278687-01) and The Mark Foundation for Cancer Research. Hamilton et al. "A proteogenomic sufaceome study identifies DLK1 as an immunotherapeutic target in neuroblastoma." Cancer Cell. Online October 24, 2024. DOI:10.1016/j.ccell.2024.10.003. About Children's Hospital of Philadelphia: A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey, as well as the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia. In addition, its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit . Contact: Jennifer Lee Children's Hospital of Philadelphia (267) 426-6084 [email protected] SOURCE Children's Hospital of Philadelphia WANT YOUR COMPANY'S NEWS FEATURED ON PRNEWSWIRE.COM? 440k+ Newsrooms & Influencers 9k+ Digital Media Outlets 270k+ Journalists Opted In GET STARTED

免疫疗法临床1期

2024-07-30

·生物探索

Immunity | 刘强团队发现脑卒中加速动脉粥样硬化的新机制

引言脑卒中防治数据显示，我国高达40%的门诊脑卒中患者是复发人群。脑卒中后1年17.1%的患者再发脑卒中或其他血管性事件，5年复发率超过 30.0%。脑卒中复发使致残率或死亡风险相对于未复发患者增加约9.4倍。即使接受二级预防治疗，脑卒中后3个月仍有3～6%患者出现复发。因此，针对部分患者无法从已有治疗手段获益这一临床难点，明确脑卒中的复发残余风险对于脑卒中的防治具有重要意义。血管炎症可驱动动脉粥样硬化进展，导致管腔狭窄或斑块脱落形成栓子，是脑卒中复发的主要残余风险之一。然而，脑卒中后发生血管炎症和动脉粥样硬化进展的免疫学机制至今仍不清楚。因此，明确脑卒中的炎症残余风险，推动研究证据向临床指南推荐和转化，是降低这类残余风险，促进脑卒中防治的重点工作方向之一。血管内皮细胞是血液循环与血管壁之间的重要屏障，不仅维持血管壁完整性，而且感受来自循环血液中的机械和化学刺激。血管内皮细胞激活和免疫细胞粘附是动脉粥样硬化形成和进展的主要原因。脑卒中激活免疫系统，但是目前还不清楚脑卒中对血管内皮细胞和动脉粥样硬化进展的长期影响。 2024年7月29日，天津医科大学总医院刘强教授课题组在Immunity上，在线发表了题为“Brain ischemia causes systemic Notch1 activity in endothelial cells to drive atherosclerosis”的论文。课题组使用脑卒中患者队列、单细胞测序、双光子成像和流式细胞术，发现脑卒中后受损的脑组织可持续激活机体血管内皮细胞，导致单核细胞等髓系细胞粘附，从而加速脑卒中后动脉粥样硬化进展，增加脑卒中复发风险。课题组使用脑卒中患者登记队列发现动脉粥样硬化导致的管腔狭窄、斑块脱落造成的栓塞和小血管闭塞是导致脑卒中发病后在3个月内复发的主要因素。结合PET-CT和结合双光子成像等技术，发现脑缺血造成外周血管内皮细胞处于持续性激活和老化状态，从而上调免疫粘附分子VCAM1，导致单核细胞和中性粒细胞粘附明显增加。课题组使用卒中患者样本，结合单细胞测序分析和蛋白组芯片检测发现，卒中后受损的脑组织可通过外泌体持续释放Notch1受体配体DLL1和Jagged1，激活外周血管内皮细胞Notch1通路，造成血管炎症和加速动脉粥样硬化进展。使用抗体药物阻断粘附分子VCAM1或Notch1受体，可延缓脑卒中后动脉粥样硬化进展（图1）。在此基础上，课题组提出通过评估脑卒中患者外周血DLL1和Jagged1，预测脑卒中后动脉粥粥样硬化进展的新策略，以及通过靶向粘附分子VCAM1和Notch1受体的免疫干预，延缓脑卒中后动脉粥样硬化进展的新理念。刘强课题组专注于脑疾病的免疫机制和临床免疫干预研究，系统揭示了免疫系统在脑卒中和神经免疫疾病等不同类型脑疾病中的病理作用及其干预手段。主持开展了靶向骨髓免疫，治疗脑疾病的多中心临床研究（NCT05154734，NCT05369351，NCT05792462），研发了靶向骨髓免疫新靶点的全人源化B细胞刺激因子受体抗体（ZL202311250418.3）和CAR-T细胞（ZL20231321640.8），并开展了临床IIT研究，有潜力使更多患者获益，具有广阔的应用前景。图1. 脑卒中加速外周动脉粥样硬化进展的模式图（Credit: Immunity）左图：脑卒中后小胶质细胞等脑内细胞释放含有Notch1受体配体DLL1和Jagged1的外泌体，激活外周血管内皮细胞Notch1信号通路，导致系统性血管内皮细胞活化和衰老，造成单核细胞和中性粒细胞粘附，从而加速动脉粥样硬化进展，增加脑卒中再发风险。右图：《Immunity》封面图候选。脑卒中后脑内的释放含有Notch1配体的外泌体好似山上的落石，坠落后导致山路交通堵塞，从而加速动脉粥样硬化进展和卒中复发。参考文献 https://doi.org/10.1016/j.immuni.2024.07.002 责编|探索君排版|探索君文章来源|“BioArt” End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

2024-04-22

·生物制药小编

非小细胞肺癌新靶点：Jagged2

非小细胞肺癌占所有肺癌病例的近85%。然而，虽然像K药等免疫疗法已经改变了非小细胞肺癌的治疗格局，然而，仍有一部分患者对这些治疗方案没有反应。近日，一项来自墨菲特癌症治疗中心的研究揭示了这个问题的答案，深入了解了肺癌细胞如何逃避人体的免疫系统，这一发现有可能为基于抗体的新型免疫疗法打开一扇门。相关成果发表于《Immunity》上。 Jagged2是Notch的配体，可以编码JAG2基因。这种分子在促进肺癌的侵袭性和免疫逃避能力方面起着主要作用。临床中许多Jagged2水平较高的肿瘤与预后较差和免疫力下降有关。因此研究人员由此打算调查Jagged2与肿瘤水平之间的联系。研究人员特别采用了阴性的JAG2−/−肺部肿瘤模型，表现出更高频率的巨噬细胞表达免疫刺激介质并触发T细胞依赖性抗肿瘤免疫。从肺癌细胞中去除Jagged2或使用识别Jagged2的抗体会导致肿瘤生长速度减慢，并增加巨噬细胞介导的保护性免疫细胞活性。从机理上来看，阻断Jagged2会触发巨噬细胞接收来自分子DLL1和DLL4的信号，进而激活Notch信号通路并驱动IRF4然后，这些巨噬细胞瞄准并消灭癌细胞。（如下图所示）总的来说，这一发现可能成为肺癌治疗的新机遇。目前研究小组正在探索针对Jagged2的最有效方法，并在临床实践中与免疫疗法相结合。参考来源：Jay K. Mandula et al, Jagged2 targeting in lung cancer activates anti-tumor immunity via Notch-induced functional reprogramming of tumor-associated macrophages, Immunity (2024). DOI: 10.1016/j.immuni.2024.03.020 内容来源于网络，如有侵权，请联系删除。

免疫疗法