An antibody to Notch3 reverses the skeletal phenotype of lateral meningocele syndrome in male mice

Yu, Jungeun; Siebel, Christian W.; Schilling, Lauren; Canalis, Ernesto

doi:10.1002/jcp.28960

Cited by 23 publications

(20 citation statements)

References 53 publications

(87 reference statements)

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“…Moreover, ubiquitous inhibition of NOTCH signaling might even be protumorigenic in some tissues ( Nowell and Radtke, 2017 ). Therefore, we aimed to target NOTCH3 in a more direct manner and treated AOM-induced Trp53 ΔIEC Akt E17K mice with a NOTCH3 antagonist antibody (α-NRR3; Yu et al, 2020 ). α-NRR3 targets the negative regulatory region (NRR) of the NOTCH3 receptor that prevents proteolytic cleavage and subsequent activation of the NOTCH3 receptor ( Choy et al, 2017 ; Li et al, 2008 ).…”

Section: Resultsmentioning

confidence: 99%

AKT-dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer

Varga

Nicolas

Petrocelli

et al. 2020

Journal of Experimental Medicine

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Recently, a transcriptome-based consensus molecular subtype (CMS) classification of colorectal cancer (CRC) has been established, which may ultimately help to individualize CRC therapy. However, the lack of animal models that faithfully recapitulate the different molecular subtypes impedes adequate preclinical testing of stratified therapeutic concepts. Here, we demonstrate that constitutive AKT activation in intestinal epithelial cells markedly enhances tumor invasion and metastasis in Trp53ΔIEC mice (Trp53ΔIECAktE17K) upon challenge with the carcinogen azoxymethane. Gene-expression profiling indicates that Trp53ΔIECAktE17K tumors resemble the human mesenchymal colorectal cancer subtype (CMS4), which is characterized by the poorest survival rate among the four CMSs. Trp53ΔIECAktE17K tumor cells are characterized by Notch3 up-regulation, and treatment of Trp53ΔIECAktE17K mice with a NOTCH3-inhibiting antibody reduces invasion and metastasis. In CRC patients, NOTCH3 expression correlates positively with tumor grading and the presence of lymph node as well as distant metastases and is specifically up-regulated in CMS4 tumors. Therefore, we suggest NOTCH3 as a putative target for advanced CMS4 CRC patients.

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Section: Resultsmentioning

confidence: 99%

AKT-dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer

Varga

Nicolas

Petrocelli

et al. 2020

Journal of Experimental Medicine

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“…4d , e ). Further, twice weekly treatment with a NOTCH3 antagonizing antibody (anti-NRR3) 21 attenuated arthritis severity (p=3.47×10 −8 ) and joint swelling (p=5.54×10 −9 ) compared to treatment with an isotype control antibody ( Fig. 4f , g ).…”

Section: Notch3 Blockade Attenuates Inflammatory Arthritismentioning

confidence: 95%

Notch signalling drives synovial fibroblast identity and arthritis pathology

Wei

Korsunsky

Marshall

et al. 2020

Nature

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323

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The synovium is a mesenchymal tissue composed mainly of fibroblasts with a lining and sublining that surrounds the joints. In rheumatoid arthritis (RA), the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive and destroys the joint 1 , 2 . Recently, we and others found that a subset of fibroblasts located in the sublining undergoes major expansion in RA and is linked to disease activity 3 , 4 , 5 . However, the molecular mechanism by which these fibroblasts differentiate and expand in RA remains unknown. Here, we identified a critical role for NOTCH3 signaling in the differentiation of perivascular and sublining CD90( THY1 )+ fibroblasts. Using single cell RNA-sequencing and synovial tissue organoids, we found that NOTCH3 signaling drives both transcriptional and spatial gradients in fibroblasts emanating from vascular endothelial cells outward. In active RA, NOTCH3 and NOTCH target genes are markedly upregulated in synovial fibroblasts. Importantly, genetic deletion of Notch3 or monoclonal antibody-blockade of NOTCH3 signaling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit positional identity regulated by endothelium-derived Notch signaling and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis.

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“…LMS is often associated with Neurofibromatosis type 1, although the genetic background for the coappearance of both diseases is elusive [ 114 ]. In a murine model for LMS, Yu et al were able to reverse the skeletal phenotype (osteopenia) of LMS by applying an antibody directed against the NRR of receptor Notch3 [ 118 ].…”

Section: Pathologic Mutations In Notch Signalingmentioning

confidence: 99%

Relevance of Notch Signaling for Bone Metabolism and Regeneration

Ballhause

Jiang

Baranowsky

et al. 2021

IJMS

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Notch1-4 receptors and their signaling pathways are expressed in almost all organ systems and play a pivotal role in cell fate decision by coordinating cell proliferation, differentiation and apoptosis. Differential expression and activation of Notch signaling pathways has been observed in a variety of organs and tissues under physiological and pathological conditions. Bone tissue represents a dynamic system, which is constantly remodeled throughout life. In bone, Notch receptors have been shown to control remodeling and regeneration. Numerous functions have been assigned to Notch receptors and ligands, including osteoblast differentiation and matrix mineralization, osteoclast recruitment and cell fusion and osteoblast/osteoclast progenitor cell proliferation. The expression and function of Notch1-4 in the skeleton are distinct and closely depend on the temporal expression at different differentiation stages. This review addresses the current knowledge on Notch signaling in adult bone with emphasis on metabolism, bone regeneration and degenerative skeletal disorders, as well as congenital disorders associated with mutant Notch genes. Moreover, the crosstalk between Notch signaling and other important pathways involved in bone turnover, including Wnt/β-catenin, BMP and RANKL/OPG, are outlined.

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An antibody to Notch3 reverses the skeletal phenotype of lateral meningocele syndrome in male mice

Cited by 23 publications

References 53 publications

AKT-dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer

AKT-dependent NOTCH3 activation drives tumor progression in a model of mesenchymal colorectal cancer

Notch signalling drives synovial fibroblast identity and arthritis pathology

Relevance of Notch Signaling for Bone Metabolism and Regeneration

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