title: Defining stem cell dynamics in models of intestinal tumor initiation.
abstract: Cancer is a disease in which cells accumulate genetic aberrations that are believed to confer a clonal advantage over cells in the surrounding tissue. However, the quantitative benefit of frequently occurring mutations during tumor development remains unknown. We quantified the competitive advantage of Apc loss, Kras activation, and P53 mutations in the mouse intestine. Our findings indicate that the fate conferred by these mutations is not deterministic, and many mutated stem cells are replaced by wild-type stem cells after biased, but still stochastic events. Furthermore, P53 mutations display a condition-dependent advantage, and especially in colitis-affected intestines, clones harboring mutations in this gene are favored. Our work confirms the previously theoretical notion that the tissue architecture of the intestine suppresses the accumulation of mutated lineages.
authors.affiliation: Cancer Research UK, Cambridge Institute, University of Cambridge, Robinson Way, Cambridge CB2 0RE, UK.
authors.forename: Louis
authors.initials: L
authors.lastname: Vermeulen
authors.forename: Edward
authors.initials: E
authors.lastname: Morrissey
authors.forename: Maartje
authors.initials: M
authors.lastname: van der Heijden
authors.forename: Anna M
authors.initials: AM
authors.lastname: Nicholson
authors.forename: Andrea
authors.initials: A
authors.lastname: Sottoriva
authors.forename: Simon
authors.initials: S
authors.lastname: Buczacki
authors.forename: Richard
authors.initials: R
authors.lastname: Kemp
authors.forename: Simon
authors.initials: S
authors.lastname: Tavaré
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Winton
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics* / Q000473:pathology*; D015972:Gene Expression Regulation, Neoplastic; D007414:Intestinal Neoplasms / Q000235:genetics* / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D008954:Models, Biological; D009154:Mutation; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D015533:Transcriptional Activation; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D016159:Tumor Suppressor Protein p53; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)