title: TALEN-mediated apc mutation in Xenopus tropicalis phenocopies familial adenomatous polyposis.
abstract: Truncating mutations in the tumor suppressor gene adenomatous polyposis coli (APC) are the initiating step in the vast majority of sporadic colorectal cancers, and they underlie familial adenomatous polyposis (FAP) syndromes. Modeling of APC- driven tumor formation in the mouse has contributed substantially to our mechanistic understanding of the associated disease, but additional models are needed to explore therapeutic opportunities and overcome current limitations of mouse models. We report on a novel and penetrant genetic cancer model in Xenopus tropicalis, an aquatic tetrapod vertebrate with external development, diploid genome and short life cycle. Tadpoles and froglets derived from embryos injected with TAL effector nucleases targeting the apc gene rapidly developed intestinal hyperplasia and other neoplasms observed in FAP patients, including desmoid tumors and medulloblastomas. Bi-allelic apc mutations causing frame shifts were detected in the tumors, which displayed activation of the Wnt/β-catenin pathway and showed increased cellular proliferation. We further demonstrate that simultaneous double bi-allelic mutation of apc and a non-relevant gene is possible in the neoplasias, opening the door for identification and characterization of effector or modifier genes in tumors expressing truncated apc. Our results demonstrate the power of modeling human cancer in Xenopus tropicalis using mosaic TALEN-mediated bi-allelic gene disruption.
authors.affiliation: Developmental Biology Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Tom
authors.initials: T
authors.lastname: Van Nieuwenhuysen
authors.affiliation: Developmental Biology Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: Naert
authors.affiliation: Developmental Biology Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Hong Thi
authors.initials: HT
authors.lastname: Tran
authors.affiliation: Developmental Biology Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Griet
authors.initials: G
authors.lastname: Van Imschoot
authors.affiliation: Developmental Biology Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Geurs
authors.affiliation: Molecular Cell Biology Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium ; Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium.
authors.forename: Ellen
authors.initials: E
authors.lastname: Sanders
authors.affiliation: Department of Pathology, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: David
authors.initials: D
authors.lastname: Creytens
authors.affiliation: Molecular Cell Biology Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium ; Inflammation Research Center, Flanders Institute for Biotechnology (VIB), Ghent, Belgium.
authors.forename: Frans
authors.initials: F
authors.lastname: Van Roy
authors.affiliation: Developmental Biology Unit, Department of Biomedical Molecular Biology, Ghent University, Ghent, Belgium ; Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium.
authors.forename: Kris
authors.initials: K
authors.lastname: Vleminckx
keywords: APC; Intestinal cancer; Wnt signaling; animal model; desmoid tumors