Manic Fringe deficiency imposes Jagged1 addiction to intestinal tumor cells

Erika López-Arribillaga, Verónica Rodilla, Carlota Colomer, Anna Vert, Amy Shelton, Jason H. Cheng, Bing Yan, Abel Gonzalez-Perez, Melissa R. Junttila, Mar Iglesias, Ferran Torres, Joan Albanell, Alberto Villanueva, Anna Bigas (), Christian W. Siebel () and LLuís Espinosa ()
Additional contact information
Erika López-Arribillaga: Cancer Research Program. CIBERONC. Institut Mar d’Investigacions Mèdiques, Hospital del Mar
Verónica Rodilla: Cancer Research Program. CIBERONC. Institut Mar d’Investigacions Mèdiques, Hospital del Mar
Carlota Colomer: Cancer Research Program. CIBERONC. Institut Mar d’Investigacions Mèdiques, Hospital del Mar
Anna Vert: Cancer Research Program. CIBERONC. Institut Mar d’Investigacions Mèdiques, Hospital del Mar
Amy Shelton: Genentech, Inc.
Jason H. Cheng: Genentech, Inc.
Bing Yan: Cancer Research Program. CIBERONC. Institut Mar d’Investigacions Mèdiques, Hospital del Mar
Abel Gonzalez-Perez: IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra
Melissa R. Junttila: Genentech, Inc., 1 DNA Way, South San Francisco
Mar Iglesias: Hospital del Mar
Ferran Torres: Universitat Autonoma of Barcelona
Joan Albanell: Cancer Research Program. CIBERONC. Institut Mar d’Investigacions Mèdiques, Hospital del Mar
Alberto Villanueva: IDIBELL-Institut Català d’Oncologia Gran Via km 2.7, Hospitalet
Anna Bigas: Cancer Research Program. CIBERONC. Institut Mar d’Investigacions Mèdiques, Hospital del Mar
Christian W. Siebel: Genentech, Inc.
LLuís Espinosa: Cancer Research Program. CIBERONC. Institut Mar d’Investigacions Mèdiques, Hospital del Mar

Nature Communications, 2018, vol. 9, issue 1, 1-13

Abstract: 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.

Date: 2018
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DOI: 10.1038/s41467-018-05385-0

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