Manic fringe deficiency imposes jagged1 addiction to intestinal tumor cells

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• dc.contributor.author López Arribillaga, Erika, 1986-
• dc.contributor.author Rodilla, Verónica
• dc.contributor.author Colomer Montañà, Carlota, 1990-
• dc.contributor.author Vert, Anna
• dc.contributor.author Shelton, Amy
• dc.contributor.author Cheng, Jason H.
• dc.contributor.author Yan, Bing
• dc.contributor.author Gonzalez-Perez, Abel
• dc.contributor.author Junttila, Melissa R.
• dc.contributor.author Iglesias Coma, Mar
• dc.contributor.author Torres, Ferran
• dc.contributor.author Albanell Mestres, Joan
• dc.contributor.author Villanueva, Alberto
• dc.contributor.author Bigas Salvans, Anna
• dc.contributor.author Siebel, Christian W.
• dc.contributor.author Espinosa Blay, Lluís
• dc.date.accessioned 2019-06-14T07:39:32Z
• dc.date.available 2019-06-14T07:39:32Z
• dc.date.issued 2018
• dc.description.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.
• dc.format.mimetype application/pdf
• dc.identifier.citation López-Arribillaga E, Rodilla V, Colomer C, Vert A, Shelton A, Cheng JH et al. Manic fringe deficiency imposes jagged1 addiction to intestinal tumor cells. Nat Commun. 2018 Jul 31;9(1):2992. DOI: 10.1038/s41467-018-05385-0
• dc.identifier.doi http://dx.doi.org/10.1038/s41467-018-05385-0
• dc.identifier.issn 2041-1723
• dc.identifier.uri http://hdl.handle.net/10230/41754
• dc.language.iso eng
• dc.publisher Nature Research
• dc.relation.ispartof Nature Communications. 2018 Jul 31;9(1):2992
• dc.rights copyright © The Author(s) 2018. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.other Intestins -- Càncer
• dc.subject.other Intestins -- Malalties
• dc.title Manic fringe deficiency imposes jagged1 addiction to intestinal tumor cells
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion