Engineered patterns of Notch ligands Jag1 and Dll4 elicit differential spatial control of endothelial sprouting

Tiemeijer, Laura A.; Ristori, Tommaso; Stassen, Oscar M. J. A.; Ahlberg, Jaakko J.; Bijl, Jonne J.J. de; Chen, Christopher; Bentley, Katie; Bouten, Cvc Carlijn; Sahlgren, Cecilia

doi:10.1016/j.isci.2022.104306

Cited by 13 publications

(12 citation statements)

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“…They regulate the proliferation of regulatory T cells (7,9), influence tumor microenvironment, promote adipocyte differentiation (29), mediate hematopoietic cell differentiation (30) and neurogenesis (31). Moreover, Jag1 overexpression in cancer cells can activate Notch signaling in adjacent endothelial cells (32). Our study focused on NICD expression, however did not underestimate the role of tumor microenvironment.…”

Section: Discussionmentioning

confidence: 97%

Notch-Jagged1 signaling and response to bevacizumab therapy in advanced colorectal cancer: A glance to radiomics or back to physiopathology?

Negri

Bottarelli²,

Pedrazzi³

et al. 2023

Front. Oncol.

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IntroductionThe Notch intracellular domain (NICD) and its ligands Jagged-1(Jag1), Delta-like ligand (DLL-3) and DLL4 play an important role in neoangiogenesis. Previous studies suggest a correlation between the tissue levels of NICD and response to therapy with bevacizumab in colorectal cancer (CRC). Another marker that may predict outcome in CRC is radiomics of liver metastases. The aim of this study was to investigate the expression of NICD and its ligands and the role of radiomics in the selection of treatment-naive metastatic CRC patients receiving bevacizumab.MethodsImmunohistochemistry (IHC) for NICD, Jag1 and E-cadherin was performed on the tissue microarrays (TMAs) of 111 patients with metastatic CRC treated with bevacizumab and chemotherapy. Both the intensity and the percentage of stained cells were evaluated. The absolute number of CD4+ and CD8+ lymphocytes was counted in three different high-power fields and the mean values obtained were used to determine the CD4/CD8 ratio. The positivity of tumor cells to DLL3 and DLL4 was studied. The microvascular density (MVD) was assessed in fifteen cases by counting the microvessels at 20x magnification and expressed as MVD score. Abdominal CT scans were retrieved and imported into a dedicated workstation for radiomic analysis. Manually drawn regions of interest (ROI) allowed the extraction of radiomic features (RFs) from the tumor.ResultsA positive association was found between NICD and Jag1 expression (p < 0.001). Median PFS was significantly shorter in patients whose tumors expressed high NICD and Jag1 (6.43 months vs 11.53 months for negative cases; p = 0.001). Those with an MVD score ≥5 (CD31-high, NICD/Jag1 positive) experienced significantly poorer survival. The radiomic model developed to predict short and long-term survival and PFS yielded a ROC-AUC of 0.709; when integrated with clinical and histopathological data, the integrated model improved the predictive score (ROC-AUC of 0.823).DiscussionThese results show that high NICD and Jag1 expression are associated with progressive disease and early disease progression to anti VEGF-based therapy; the preliminary radiomic analyses show that the integration of quantitative information with clinical and histological data display the highest performance in predicting the outcome of CRC patients.

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Section: Discussionmentioning

confidence: 97%

Notch-Jagged1 signaling and response to bevacizumab therapy in advanced colorectal cancer: A glance to radiomics or back to physiopathology?

Negri

Bottarelli²,

Pedrazzi³

et al. 2023

Front. Oncol.

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“…The ODEs are deterministic, but the final solutions depend on the initial conditions because of the multiple attractors present in the solution space and the limited simulation time. To account for this, similar to previous studies with analogous Notch models (Boareto, Jolly, Lu, et al ., 2015; Loerakker et al ., 2018; Ristori et al ., 2020; Tiemeijer et al ., 2022), the simulations were performed for 10000 random initial conditions. Simulations were performed for 10 adjacent cells with periodic boundary conditions, as in a recent study (Tiemeijer et al ., 2022), such that the first cell was assumed to be interacting with the last (10 th ) cell.…”

Section: Methodsmentioning

confidence: 99%

“…To account for this, similar to previous studies with analogous Notch models (Boareto, Jolly, Lu, et al ., 2015; Loerakker et al ., 2018; Ristori et al ., 2020; Tiemeijer et al ., 2022), the simulations were performed for 10000 random initial conditions. Simulations were performed for 10 adjacent cells with periodic boundary conditions, as in a recent study (Tiemeijer et al ., 2022), such that the first cell was assumed to be interacting with the last (10 th ) cell. For more details on the specific ODEs, we refer the reader to the Supplementary Information.…”

Section: Methodsmentioning

confidence: 99%

Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe

Ristori,

Thuret,

Hooker

et al. 2023

Preprint

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SummaryIn briefThe mechanisms regulating the signaling pathways involved in angiogenesis are not fully known. Ristori et al. show that Lunatic Fringe (LFng) mediates the crosstalk between Bone Morphogenic Protein 9 (Bmp9) and Notch signaling, thereby regulating the endothelial cell behavior and temporal dynamics of their identity during sprouting angiogenesis.HighlightsBmp9 upregulates the expression of LFng in endothelial cells.LFng regulates the temporal dynamics of tip/stalk selection and rearrangement.LFng indicated to play a role in hereditary hemorrhagic telangiectasia.Bmp9 and LFng mediate the endothelial cell-pericyte crosstalk.Bone Morphogenic Protein 9 (Bmp9), whose signaling through Activin receptor-like kinase 1 (Alk1) is involved in several diseases, has been shown to independently activate Notch target genes in an additive fashion with canonical Notch signaling. Here, by integrating predictive computational modeling validated with experiments, we uncover that Bmp9 upregulates Lunatic Fringe (LFng) in endothelial cells (ECs), and thereby also regulates Notch activity in an inter-dependent, multiplicative fashion. Specifically, the Bmp9-upregulated LFng enhances Notch receptor activity creating a much stronger effect when Dll4 ligands are also present. During sprouting, this LFng regulation alters vessel branching by modulating the timing of EC phenotype selection and rearrangement. Our results further indicate that LFng can play a role in Bmp9-related diseases and in pericyte-driven vessel stabilization, since we find LFng contributes to Jag1 upregulation in Bmp9-stimulated ECs; thus, Bmp9-upregulated LFng results in not only enhanced EC Dll4-Notch1 activation, but also Jag1-Notch3 activation in pericytes.

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“…Protein degradation is described with the degradation parameters and I . Analogous to a previous approach (Tiemeijer and Ristori et al 2022a), Eqs. ( 27) and (30) were modified from earlier works (Loerakker et al 2018;van Engeland et al 2019;Ristori et al 2021;Van Asten and Ristori et al 2022) to incorporate effects of external Jagged ligands, either soluble ( J sol ) or immobilized to a surface ( J im ).…”

Section: Notch Signaling Modelmentioning

confidence: 97%

A multiscale computational model of arterial growth and remodeling including Notch signaling

Asten

Latorre

Karakaya

et al. 2023

Biomech Model Mechanobiol

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Blood vessels grow and remodel in response to mechanical stimuli. Many computational models capture this process phenomenologically, by assuming stress homeostasis, but this approach cannot unravel the underlying cellular mechanisms. Mechano-sensitive Notch signaling is well-known to be key in vascular development and homeostasis. Here, we present a multiscale framework coupling a constrained mixture model, capturing the mechanics and turnover of arterial constituents, to a cell–cell signaling model, describing Notch signaling dynamics among vascular smooth muscle cells (SMCs) as influenced by mechanical stimuli. Tissue turnover was regulated by both Notch activity, informed by in vitro data, and a phenomenological contribution, accounting for mechanisms other than Notch. This novel framework predicted changes in wall thickness and arterial composition in response to hypertension similar to previous in vivo data. The simulations suggested that Notch contributes to arterial growth in hypertension mainly by promoting SMC proliferation, while other mechanisms are needed to fully capture remodeling. The results also indicated that interventions to Notch, such as external Jagged ligands, can alter both the geometry and composition of hypertensive vessels, especially in the short term. Overall, our model enables a deeper analysis of the role of Notch and Notch interventions in arterial growth and remodeling and could be adopted to investigate therapeutic strategies and optimize vascular regeneration protocols.

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Engineered patterns of Notch ligands Jag1 and Dll4 elicit differential spatial control of endothelial sprouting

Cited by 13 publications

References 55 publications

Notch-Jagged1 signaling and response to bevacizumab therapy in advanced colorectal cancer: A glance to radiomics or back to physiopathology?

Notch-Jagged1 signaling and response to bevacizumab therapy in advanced colorectal cancer: A glance to radiomics or back to physiopathology?

Bmp9 regulates Notch signaling and the temporal dynamics of angiogenesis via Lunatic Fringe

A multiscale computational model of arterial growth and remodeling including Notch signaling

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