title: Indispensable role of Notch ligand-dependent signaling in the proliferation and stem cell niche maintenance of APC-deficient intestinal tumors.
abstract: Ligand-dependent activation of Notch signaling is required to maintain the stem-cell niche of normal intestinal epithelium. However, the precise role of Notch signaling in the maintenance of the intestinal tumor stem cell niche and the importance of the RBPJ-independent non-canonical pathway in intestinal tumors remains unknown. Here we show that Notch signaling was activated in LGR5+vecells of APC-deficient mice intestinal tumors. Accordingly, Notch ligands, including Jag1, Dll1, and Dll4, were expressed in these tumors. In vitro studies using tumor-derived organoids confirmed the intrinsic Notch activity-dependent growth of tumor cells. Surprisingly, the targeted deletion of Jag1 but not RBPJ in LGR5+vetumor-initiating cells resulted in the silencing of Hes1 expression, disruption of the tumor stem cell niche, and dramatic reduction in the proliferation activity of APC-deficient intestinal tumors in vivo. Thus, our results highlight the importance of ligand-dependent non-canonical Notch signaling in the proliferation and maintenance of the tumor stem cell niche in APC-deficient intestinal adenomas.
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Nakata
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; Department of Medicine, University of California, San Francisco, San Francisco, CA, USA.
authors.forename: Hiromichi
authors.initials: H
authors.lastname: Shimizu
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Sayaka
authors.initials: S
authors.lastname: Nagata
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; Institute of Clinical Molecular Biology, Christian-Albrechts-University Kiel, D-24105 Kiel, Germany.
authors.forename: Go
authors.initials: G
authors.lastname: Ito
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Satoru
authors.initials: S
authors.lastname: Fujii
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Suzuki
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Ami
authors.initials: A
authors.lastname: Kawamoto
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Ishibashi
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Kuno
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Anzai
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tatsuro
authors.initials: T
authors.lastname: Murano
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Mizutani
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Oshima
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Kiichiro
authors.initials: K
authors.lastname: Tsuchiya
authors.affiliation: Department of Advanced Therapeutics in GI Diseases, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Nakamura
authors.affiliation: Department of Immunology, Tokai University School of Medicine, Isehara, Japan.
authors.forename: Katsuto
authors.initials: K
authors.lastname: Hozumi
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Mamoru
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Gastroenterology and Hepatology, Graduate School, Tokyo Medical and Dental University, Tokyo, Japan; Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University, Tokyo, Japan. Electronic address: rokamoto.gast@tmd.ac.jp.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Okamoto
mesh_terms: D000236:Adenoma / Q000378:metabolism; D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics*; D000818:Animals; D049109:Cell Proliferation; D004815:Epidermal Growth Factor / Q000378:metabolism; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D007414:Intestinal Neoplasms / Q000378:metabolism*; D000072100:Jagged-1 Protein / Q000235:genetics*; D008024:Ligands; D051379:Mice; D008856:Microscopy, Fluorescence; D014411:Neoplastic Stem Cells / Q000166:cytology; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D051880:Receptors, Notch / Q000378:metabolism*; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; C493597:Lgr5 protein, mouse; D008024:Ligands; D043562:Receptors, G-Protein-Coupled; D051880:Receptors, Notch; C000613192:adenomatous polyposis coli protein, mouse; D004815:Epidermal Growth Factor
keywords: APC; Intestinal tumor; Jag1; Notch; RBPJ