Manic Fringe deficiency imposes Jagged1 addiction to intestinal tumor cells

Nature Communications
Erika López-ArribillagaLLuís Espinosa

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.

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Citations

Jan 9, 2019·Future Oncology·Erika López-ArribillagaLluís Espinosa
Apr 10, 2020·Current Pharmaceutical Design·Hao WangHong Yang
Aug 21, 2020·The Journal of Biological Chemistry·Shinako KakudaRobert S Haltiwanger
Mar 7, 2021·Cancers·Dorota AnusewiczAndrzej K Bednarek
May 11, 2021·Journal of Biomedical Science·Angelo Giuseppe CondorelliDaniele Castiglia
Dec 21, 2020·Molecular Aspects of Medicine·Kenjiroo MatsumotoRobert S Haltiwanger
Jul 1, 2020·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Meng-Xi XiuBo-Hai Kuang
Aug 24, 2021·Frontiers in Cell and Developmental Biology·Pankaj TrivediMaria Pia Felli

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Methods Mentioned

BETA
PCR
in vitro transcription
xenografts
Assay
confocal
Fluorescence

Software Mentioned

Prism
Leica Application Suite Advanced Fluorescence
cellSens Digital Imaging
ImageJ

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