Jagged1 is the pathological link between Wnt and Notch pathways in colorectal cancer

VERONICA RODILLA; ALBERTO VILLANUEVA; ANTONIA OBRADOR-HEVIA; ALEX ROBERT-MORENO; VANESSA FERNANDEZ-MAJADA; ANDREA GRILLI; NURIA LOPEZ-BIGAS; NICOLAS BELLORA; M. MAR ALBA; FERRAN TORRES; MIREIA DUÑACH; XAVIER SANJUAN; SARA GONZALEZ; THOMAS GRIDLEY; GABRIEL CAPELLA; ANNA BIGAS; LLUÍS ESPINOSA

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Lugar: Washington, DC; Año: 2009 vol. 106 p. 6315 - 6320

0027-8424

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.