title: Tumorigenic fragments of APC cause dominant defects in directional cell migration in multiple model systems.
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 reproduced in diverse experimental systems: in developing chicken embryos, mesoderm cells expressing N-APC failed to migrate normally; in amoeboid Dictyostelium, which lack endogenous APC, expressing an N-APC fragment maintained cell motility, but the cells failed to perform directional chemotaxis; and multicellular Dictyostelium slug aggregates similarly failed to perform phototaxis. We propose that N-terminal fragments of APC represent a gain-of-function mutation that causes cells within tissue to fail to migrate directionally in response to relevant guidance cues. Consistent with this idea, crypts in histologically normal tissues of APC(Min/+) intestines are overpopulated with cells, suggesting that a lack of migration might cause cell accumulation in a precancerous state.
authors.affiliation: Division of Cell and Developmental Biology, College of Life Science, University of Dundee, Dundee, DD1 5EH, Scotland, UK.
authors.forename: Scott A
authors.initials: SA
authors.lastname: Nelson
authors.forename: Zhouyu
authors.initials: Z
authors.lastname: Li
authors.forename: Ian P
authors.initials: IP
authors.lastname: Newton
authors.forename: David
authors.initials: D
authors.lastname: Fraser
authors.forename: Rachel E
authors.initials: RE
authors.lastname: Milne
authors.forename: David M A
authors.initials: DM
authors.lastname: Martin
authors.forename: David
authors.initials: D
authors.lastname: Schiffmann
authors.forename: Xuesong
authors.initials: X
authors.lastname: Yang
authors.forename: Dirk
authors.initials: D
authors.lastname: Dormann
authors.forename: Cornelis J
authors.initials: CJ
authors.lastname: Weijer
authors.forename: Paul L
authors.initials: PL
authors.lastname: Appleton
authors.forename: Inke S
authors.initials: IS
authors.lastname: Näthke
mesh_terms: D011125:Adenomatous Polyposis Coli / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein / Q000737:chemistry* / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000378:metabolism / Q000473:pathology*; D002642:Chick Embryo; D004023:Dictyostelium / Q000166:cytology / Q000378:metabolism; D020895:Enterocytes / Q000378:metabolism / Q000473:pathology; D005260:Female; D005799:Genes, Dominant; D007421:Intestine, Small / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D010446:Peptide Fragments / Q000378:metabolism*; D054240:Primitive Streak / Q000378:metabolism / Q000473:pathology
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D010446:Peptide Fragments