Endothelial Notch1 Activity Facilitates Metastasis

Elfriede Wieland, Juan Rodriguez-Vita, Sven S. Liebler, Carolin Mogler, Iris Moll, Stefanie E. Herberich, Elisa Espinet, Esther Herpel, Amitai Menuchin, Jenny Chang-Claude, Michael Hoffmeister, Christoffer Gebhardt, Hermann Brenner, Andreas Trumpp, Christian W. Siebel, Markus Hecker, Jochen Utikal, David Sprinzak, Andreas Fischer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Endothelial cells (ECs) provide angiocrine factors orchestrating tumor progression. Here, we show that activated Notch1 receptors (N1ICD) are frequently observed in ECs of human carcinomas and melanoma, and in ECs of the pre-metastatic niche in mice. EC N1ICD expression in melanoma correlated with shorter progression-free survival. Sustained N1ICD activity induced EC senescence, expression of chemokines and the adhesion molecule VCAM1. This promoted neutrophil infiltration, tumor cell (TC) adhesion to the endothelium, intravasation, lung colonization, and postsurgical metastasis. Thus, sustained vascular Notch signaling facilitates metastasis by generating a senescent, pro-inflammatory endothelium. Consequently, treatment with Notch1 or VCAM1-blocking antibodies prevented Notch-driven metastasis, and genetic ablation of EC Notch signaling inhibited peritoneal neutrophil infiltration in an ovarian carcinoma mouse model.

Original languageEnglish
Pages (from-to)355-367
Number of pages13
JournalCancer Cell
Volume31
Issue number3
DOIs
StatePublished - 13 Mar 2017

Funding

FundersFunder number
Dietmar Hopp Foundation
Helmholtz Society
National Center for Tumor Diseases
Deutsches Krebsforschungszentrum
Deutsche ForschungsgemeinschaftBR 1704/6-3, BR 1704/6-1, FOR 2033, CH 117/1-1, BR 1704/6-4
Universität Heidelberg
Ministry of Science, Technology and Space
Bundesministerium für Bildung und Forschung01KH0404, 01ER0814
Deutsche Krebshilfe
Nationales Centrum für Tumorerkrankungen Heidelberg

    Keywords

    • Notch signaling
    • angiogenesis
    • endothelial cell
    • extravasation
    • intravasation
    • metastasis
    • mouse models
    • neutrophils
    • senescence
    • vascular biology

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