5 years ago

Non-canonical NOTCH3 signalling limits tumour angiogenesis

Non-canonical NOTCH3 signalling limits tumour angiogenesis
Pierre Saintigny, Ana Negulescu, Shuheng Lin, Olivier Meurette, Sirisha Bulusu, Patrick Mehlen, Nicolas Gadot, Nicolas Rama, Benjamin Ducarouge, Isabelle Treilleux, Jean-Guy Delcros, Benjamin Gibert
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.

Publisher URL: https://www.nature.com/articles/ncomms16074

DOI: 10.1038/ncomms16074

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