Manic Fringe deficiency imposes Jagged1 addiction to intestinal tumor cells

Erika López-Arribillaga,Erika López-Arribillaga,Anna Bigas,Anna Bigas,Melissa R Junttila,Abel Gonzalez-Perez,Mar Iglesias,Mar Iglesias,Verónica Rodilla,Verónica Rodilla,Alberto Villanueva,Alberto Villanueva,Ferran Torres,Anna Vert,Joan Albanell,Joan Albanell,Joan Albanell,Christian W Siebel,Lluís Espinosa,Lluís Espinosa,Carlota Colomer,Amy Shelton,Jason H Cheng,Anna Vert,Carlota Colomer,Bing Yan,Bing Yan

doi:10.1038/s41467-018-05385-0

Abstract

Delta ligands regulate Notch signaling in normal intestinal stem cells, while Jagged1 activates Notch in intestinal adenomas carrying active β-catenin. We used the ApcMin/+ mouse model, tumor spheroid cultures, and patient-derived orthoxenografts to address this divergent ligand-dependent Notch function and its implication in disease. We found that intestinal-specific Jag1 deletion or antibody targeting Jag1 prevents tumor initiation in mice. Addiction to Jag1 is concomitant with the absence of Manic Fringe (MFNG) in adenoma cells, and its ectopic expression reverts Jag1 dependence. In 239 human colorectal cancer patient samples, MFNG imposes a negative correlation between Jag1 and Notch, being high Jag1 in the absence of MFNG predictive of poor prognosis. Jag1 antibody treatment reduces patient-derived tumor orthoxenograft growth without affecting normal intestinal mucosa. Our data provide an explanation to Jag1 dependence in cancer, and reveal that Jag1–Notch1 interference provides therapeutic benefit in a subset of colorectal cancer and FAP syndrome patients.

Highlights

Delta ligands regulate Notch signaling in normal intestinal stem cells, while Jagged[1] activates Notch in intestinal adenomas carrying active β-catenin
We previously reported that heterozygous deletion of Jag[1] reduced adenoma cell proliferation and tumor size in ApcMin/+ mice without affecting tumor number[29]
In the composite ApcMin/+ mice, most Jag[1] WT adenomas showed high levels of nuclear ICN1 (Fig. 1c) and total and nuclear Notch[2] (Supplementary Fig. 1F) mainly restricted to the epithelial component, compared to the levels detected in tumors lacking Jag[1]

Summary

Introduction

Delta ligands regulate Notch signaling in normal intestinal stem cells, while Jagged[1] activates Notch in intestinal adenomas carrying active β-catenin. Apc loss activates Wnt/ β-catenin that critically regulates intestinal stem cells (ISCs)[3,4] and tumor initiation[5]. We previously identified Jag1–Notch signaling as an important link between Wnt and intestinal cancer, with Jag[1] as both a transcriptional target of β-catenin and a Notch signal inducer in Apc-mutant adenomas. Therapeutic antibodies, and organoid/tumor spheroid models, we show that epithelial Jag[1] is required for tumor initiation, stem cell marker expression, and stem cell activity of the adenoma cells, both in vitro and in vivo. JAG1 levels predict patient prognosis in the group that carries MFNG-negative tumors

Methods

Results

Conclusion