Non-canonical NOTCH3 signalling limits tumour angiogenesis

Shuheng Lin, Ana Negulescu, Sirisha Bulusu, Benjamin Gibert, Jean-Guy Delcros, Benjamin Ducarouge, Nicolas Rama, Nicolas Gadot, Isabelle Treilleux, Pierre Saintigny, Olivier Meurette () and Patrick Mehlen ()
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Shuheng Lin: Apoptosis, Cancer and Development Laboratory—Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard
Ana Negulescu: Apoptosis, Cancer and Development Laboratory—Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard
Sirisha Bulusu: Apoptosis, Cancer and Development Laboratory—Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard
Benjamin Gibert: Apoptosis, Cancer and Development Laboratory—Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard
Jean-Guy Delcros: Apoptosis, Cancer and Development Laboratory—Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard
Benjamin Ducarouge: Apoptosis, Cancer and Development Laboratory—Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard
Nicolas Rama: Apoptosis, Cancer and Development Laboratory—Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard
Nicolas Gadot: Centre Léon Bérard
Isabelle Treilleux: Centre Léon Bérard
Pierre Saintigny: Centre Léon Bérard
Olivier Meurette: Apoptosis, Cancer and Development Laboratory—Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard
Patrick Mehlen: Apoptosis, Cancer and Development Laboratory—Equipe labellisée ‘La Ligue’, LabEx DEVweCAN, Centre de Recherche en Cancérologie de Lyon, INSERM U1052-CNRS UMR5286, Université de Lyon, Centre Léon Bérard

Nature Communications, 2017, vol. 8, issue 1, 1-12

Abstract: Abstract Notch signalling is a causal determinant of cancer and efforts have been made to develop targeted therapies to inhibit the so-called canonical pathway. Here we describe an unexpected pro-apoptotic role of Notch3 in regulating tumour angiogenesis independently of the Notch canonical pathway. The Notch3 ligand Jagged-1 is upregulated in a fraction of human cancer and our data support the view that Jagged-1, produced by cancer cells, is inhibiting the apoptosis induced by the aberrant Notch3 expression in tumour vasculature. We thus present Notch3 as a dependence receptor inducing endothelial cell death while this pro-apoptotic activity is blocked by Jagged-1. Along this line, using Notch3 mutant mice, we demonstrate that tumour growth and angiogenesis are increased when Notch3 is silenced in the stroma. Consequently, we show that the well-documented anti-tumour effect mediated by γ-secretase inhibition is at least in part dependent on the apoptosis triggered by Notch3 in endothelial cells.

Date: 2017
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DOI: 10.1038/ncomms16074

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