title: Biased competition between Lgr5 intestinal stem cells driven by oncogenic mutation induces clonal expansion.
abstract: The concept of 'field cancerization' describes the clonal expansion of genetically altered, but morphologically normal cells that predisposes a tissue to cancer development. Here, we demonstrate that biased stem cell competition in the mouse small intestine can initiate the expansion of such clones. We quantitatively analyze how the activation of oncogenic K-ras in individual Lgr5(+) stem cells accelerates their cell division rate and creates a biased drift towards crypt clonality. K-ras mutant crypts then clonally expand within the epithelium through enhanced crypt fission, which distributes the existing Paneth cell niche over the two new crypts. Thus, an unequal competition between wild-type and mutant intestinal stem cells initiates a biased drift that leads to the clonal expansion of crypts carrying oncogenic mutations.
authors.affiliation: Hubrecht Institute, KNAW & University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: Hugo J
authors.initials: HJ
authors.lastname: Snippert
authors.forename: Arnout G
authors.initials: AG
authors.lastname: Schepers
authors.forename: Johan H
authors.initials: JH
authors.lastname: van Es
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Simons
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
mesh_terms: D053687:Adult Stem Cells / Q000502:physiology*; D000818:Animals; D002453:Cell Cycle; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D015179:Colorectal Neoplasms / Q000235:genetics / Q000473:pathology*; D007413:Intestinal Mucosa / Q000473:pathology; D007421:Intestine, Small / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D020125:Mutation, Missense; D009857:Oncogenes; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D055153:Stem Cell Niche
chemical_list: C493597:Lgr5 protein, mouse; D043562:Receptors, G-Protein-Coupled; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)