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XB-ART-50857
Oncoscience 2015 May 19;25:555-66. doi: 10.18632/oncoscience.166.
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TALEN-mediated apc mutation in Xenopus tropicalis phenocopies familial adenomatous polyposis.

Van Nieuwenhuysen T , Naert T , Tran HT , Van Imschoot G , Geurs S , Sanders E , Creytens D , Van Roy F , Vleminckx K .


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.

PubMed ID: 26097888
PMC ID: PMC4468341
Article link: Oncoscience


Species referenced: Xenopus tropicalis
Genes referenced: apc fap mapre1 pcna tyr

Disease Ontology terms: colorectal cancer
OMIMs: COLORECTAL CANCER; CRC [+]

Article Images: [+] show captions
References [+] :
Cathcart, COX-derived prostanoid pathways in gastrointestinal cancer development and progression: novel targets for prevention and intervention. 2011, Pubmed