Tumorigenic fragments of APC cause dominant defects in directional cell migration in multiple model systems.

Disease Models & Mechanisms
Scott A NelsonInke S Näthke

Abstract

Nonsense mutations that result in the expression of truncated, N-terminal, fragments of the adenomatous polyposis coli (APC) tumour suppressor protein are found in most sporadic and some hereditary colorectal cancers. These mutations can cause tumorigenesis by eliminating β-catenin-binding sites from APC, which leads to upregulation of β-catenin and thereby results in the induction of oncogenes such as MYC. Here we show that, in three distinct experimental model systems, expression of an N-terminal fragment of APC (N-APC) results in loss of directionality, but not speed, of cell motility independently of changes in β-catenin regulation. We developed a system to culture and fluorescently label live pieces of gut tissue to record high-resolution three-dimensional time-lapse movies of cells in situ. This revealed an unexpected complexity of normal gut cell migration, a key process in gut epithelial maintenance, with cells moving with spatial and temporal discontinuity. Quantitative comparison of gut tissue from wild-type mice and APC heterozygotes (APC(Min/+); multiple intestinal neoplasia model) demonstrated that cells in precancerous epithelia lack directional preference when moving along the crypt-villus axis. This effect was r...Continue Reading

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Citations

Nov 22, 2013·PloS One·Sara-Jane DunnJames M Osborne
Dec 15, 2015·Molecular Biology of the Cell·Kate M MillsBeric R Henderson
Jun 28, 2015·Carcinogenesis·Sergio Lamprecht, Alexander Fich
Jul 20, 2018·PloS One·Cesar A SommerGustavo Mostoslavsky
Jun 6, 2018·Molecular and Cellular Biology·Sang Bum KimJerry W Shay
Apr 20, 2017·Journal of the National Cancer Institute·Lu Zhang, Jerry W Shay
Apr 17, 2013·Journal of Cell Science·Scott Nelson, Inke S Näthke

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Methods Mentioned

BETA
transfection
two-hybrid

Software Mentioned

PSI
BLAST
Volocity
ImageJ

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