Nucleolin is expressed in human fetal brain development and reactivated in human glial brain tumors regulating angiogenesis and vascular metabolism

Trizio, Ignazio de; Shiu, Jau-Ye; Ghobrial, Moheb; Sürücü, Oǧuzkan; Girolamo, Francesco; Errede, Mariella; Yilmaz, M. Deniz; Haybaeck, Johannes; Moiraghi, Alessandro; Monnier, Philippe P.; Lawler, Sean E.; Greenfield, Jeffrey P.; Radovanović, Ivan; Frei, Karl; Schlapbach, Ralph; Vogel, Viola; Virgintino, Daniela; Bock, Katrien De; Wälchli, Thomas

doi:10.1101/2020.10.14.337824

Cited by 2 publications

(1 citation statement)

References 107 publications

(201 reference statements)

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“…Recently, we identified nucleolin, a neurodevelopmental regulator of angiogenesis in the human fetal brain vasculature, as a reactivated, positive regulator of sprouting angiogenesis in glioblastoma 254 . In our own scRNA-seq dataset, we have identified various reactivated fetal signalling pathways in human low-grade and high-grade glioma or glioblastoma with a general (non-CNS-specific) mode of action, including, cell–ECM interaction-related and cell–cell interaction-related signalling pathways, as well as WNT, BRAF, Notch, VEGF–VEGFR1 and VEGF–VEGFR2, IL-8–CXCR1, PI3K–AKT, PDGF–PDGFR, Hedgehog, angiopoietin–TIE1, angiopoietin–TIE2, ephrin and integrin signalling cascades 163 .…”

Section: Angiogenesis In Brain Tumoursmentioning

confidence: 99%

Shaping the brain vasculature in development and disease in the single-cell era

et al. 2023

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The CNS critically relies on the formation and proper function of its vasculature during development, adult homeostasis and disease. Angiogenesis — the formation of new blood vessels — is highly active during brain development, enters almost complete quiescence in the healthy adult brain and is reactivated in vascular-dependent brain pathologies such as brain vascular malformations and brain tumours. Despite major advances in the understanding of the cellular and molecular mechanisms driving angiogenesis in peripheral tissues, developmental signalling pathways orchestrating angiogenic processes in the healthy and the diseased CNS remain incompletely understood. Molecular signalling pathways of the ‘neurovascular link’ defining common mechanisms of nerve and vessel wiring have emerged as crucial regulators of peripheral vascular growth, but their relevance for angiogenesis in brain development and disease remains largely unexplored. Here we review the current knowledge of general and CNS-specific mechanisms of angiogenesis during brain development and in brain vascular malformations and brain tumours, including how key molecular signalling pathways are reactivated in vascular-dependent diseases. We also discuss how these topics can be studied in the single-cell multi-omics era.

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Section: Angiogenesis In Brain Tumoursmentioning

confidence: 99%

Shaping the brain vasculature in development and disease in the single-cell era

et al. 2023

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Onco-fetal protein Nogo-A restricts human and mouse glioma vascularization and growth via VEGF-Notch-hippo-metabolic signaling

Schwab,

Ghobrial,

Jimenez-Macia

et al. 2024

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Glioblastoma is one of the most deadly human cancers characterized by high degrees of vascularization, but targeting its vasculature has resulted in very limited success so far. Angiogenesis, the growth of new blood vessels, is highly dynamic during brain development, enters a mostly quiescent state in the adult homeostatic brain, and is reactivated in vascular-dependent CNS diseases including brain tumors. In consequence, a better understanding of the relevance of the onco-fetal axis - describing the reactivation of fetal signaling programs in tumors - in endothelial- and perivascular cells of the human brain tumor vasculature harbors great translational potential, yet remains poorly defined. In development, neurovascular link (NVL) molecules guide both neuronal growth cones as well as capillary endothelial tip cells. Nogo-A is an NVL molecule known to inhibit axonal growth in the developing and adult CNS and to restrict angiogenesis during brain development, but its role in the mouse and human brain tumor vasculature along the onco-fetal axis remains unknown. Here, we characterize Nogo-A as an onco-fetal protein expressed in the neurovascular unit (NVU) in human fetal brains and human gliomas in vivo that negatively regulates sprouting angiogenesis and endothelial tip cells in glioma vascularization. The Nogo-A-specific Delta 20 domain restricts angiogenic sprouting and branching and promotes vascular normalization while inhibiting glioma growth in experimental gliomas. Moreover, Nogo-A expression in tumor cells negatively correlate/s with glioma malignancy in vivo. In vitro, Nogo-A Delta 20 reduced human brain- and brain tumor endothelial cell (HBMVEC, HBTMVEC) and human umbilical vein endothelial cell (HUVEC) spreading, migration, and sprouting, in a dose-dependent manner and inhibited filopodia extension glucose metabolism. Mechanistically, RNA sequencing of Nogo-A Delta 20-treated HBMVECs and HBTMVECs revealed Nogo-A Delta 20-induced positive regulation of the angiogenesis-inhibiting Dll4-Notch-pathway and inhibition of the angiogenesis-promoting VEGF-VEGFR and Hippo-YAP-TAZ pathways, whereas metabolomics and functional metabolic assays revealed Nogo-A Delta 20-induced negative regulation of endothelial glycolysis in HBMVECs and HBTMVECs. These findings characterize Nogo-A as an onco-fetal protein in the human glial brain tumor vasculature and identify Nogo-A Delta 20 signaling as an important negative regulator of human glioma vascularization and growth. Enhancing Nogo-A signaling may be an attractive alternative or combinatorial anti-angiogenic therapy to restrict human glioma/glioblastoma vascularization and growth.

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Nucleolin is expressed in human fetal brain development and reactivated in human glial brain tumors regulating angiogenesis and vascular metabolism

Cited by 2 publications

References 107 publications

Shaping the brain vasculature in development and disease in the single-cell era

Shaping the brain vasculature in development and disease in the single-cell era

Onco-fetal protein Nogo-A restricts human and mouse glioma vascularization and growth via VEGF-Notch-hippo-metabolic signaling

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