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Lopez-ArribillagaE.pdf (5.21 MB)

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2018-07-31

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cc by (c) López Arribillaga et al., 2018
Please use this identifier to cite or link to this item: https://hdl.handle.net/2445/172399

Manic Fringe deficiency imposes Jagged1 addiction to intestinal tumor cells

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https://doi.org/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 beta-catenin. We used the Apc(Min/+ )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 intestinalspecific 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 patientderived tumor orthoxenograft growth without affecting normal intestinal mucosa. Our data provide an explanation to Jag1 dependence in cancer, and reveal that Jag1-Notchl interference provides therapeutic benefit in a subset of colorectal cancer and FAP syndrome patients.

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Càncer colorectal, Lligands

Subject (English)

Colorectal cancer, Ligands

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Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

Citation

LÓPEZ ARRIBILLAGA, Erika, et al. Manic Fringe deficiency imposes Jagged1 addiction to intestinal tumor cells. Nature Communications. 2018. Vol. 9. [consulted: 12 of August of 2026]. Available at: https://hdl.handle.net/2445/172399

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