title: Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer.
abstract: Notch has been linked to beta-catenin-dependent tumorigenesis; however, the mechanisms leading to Notch activation and the contribution of the Notch pathway to colorectal cancer is not yet understood. By microarray analysis, we have identified a group of genes downstream of Wnt/beta-catenin (down-regulated when blocking Wnt/beta-catenin) that are directly regulated by Notch (repressed by gamma-secretase inhibitors and up-regulated by active Notch1 in the absence of beta-catenin signaling). We demonstrate that Notch is downstream of Wnt in colorectal cancer cells through beta-catenin-mediated transcriptional activation of the Notch-ligand Jagged1. Consistently, expression of activated Notch1 partially reverts the effects of blocking Wnt/beta-catenin pathway in tumors implanted s.c. in nude mice. Crossing APC(Min/+) with Jagged1(+/Delta) mice is sufficient to significantly reduce the size of the polyps arising in the APC mutant background indicating that Notch is an essential modulator of tumorigenesis induced by nuclear beta-catenin. We show that this mechanism is operating in human tumors from Familial Adenomatous Polyposis patients. We conclude that Notch activation, accomplished by beta-catenin-mediated up-regulation of Jagged1, is required for tumorigenesis in the intestine. The Notch-specific genetic signature is sufficient to block differentiation and promote vasculogenesis in tumors whereas proliferation depends on both pathways.
authors.affiliation: Institut d'Investigació Biomèdica de Bellvitge Gran Via km 2.7, Hospitalet and Institut Municipal d'Investigacions Mèdiques-Hospital del Mar, Dr. Aiguader 88, 08003 Barcelona, Spain.
authors.forename: Verónica
authors.initials: V
authors.lastname: Rodilla
authors.forename: Alberto
authors.initials: A
authors.lastname: Villanueva
authors.forename: Antonia
authors.initials: A
authors.lastname: Obrador-Hevia
authors.forename: Alex
authors.initials: A
authors.lastname: Robert-Moreno
authors.forename: Vanessa
authors.initials: V
authors.lastname: Fernández-Majada
authors.forename: Andrea
authors.initials: A
authors.lastname: Grilli
authors.forename: Nuria
authors.initials: N
authors.lastname: López-Bigas
authors.forename: Nicolás
authors.initials: N
authors.lastname: Bellora
authors.forename: M Mar
authors.initials: MM
authors.lastname: Albà
authors.forename: Ferran
authors.initials: F
authors.lastname: Torres
authors.forename: Mireia
authors.initials: M
authors.lastname: Duñach
authors.forename: Xavier
authors.initials: X
authors.lastname: Sanjuan
authors.forename: Sara
authors.initials: S
authors.lastname: Gonzalez
authors.forename: Thomas
authors.initials: T
authors.lastname: Gridley
authors.forename: Gabriel
authors.initials: G
authors.lastname: Capella
authors.forename: Anna
authors.initials: A
authors.lastname: Bigas
authors.forename: Lluís
authors.initials: L
authors.lastname: Espinosa