title: Centrosome Amplification Is Sufficient to Promote Spontaneous Tumorigenesis in Mammals.
abstract: Centrosome amplification is a common feature of human tumors, but whether this is a cause or a consequence of cancer remains unclear. Here, we test the consequence of centrosome amplification by creating mice in which centrosome number can be chronically increased in the absence of additional genetic defects. We show that increasing centrosome number elevated tumor initiation in a mouse model of intestinal neoplasia. Most importantly, we demonstrate that supernumerary centrosomes are sufficient to drive aneuploidy and the development of spontaneous tumors in multiple tissues. Tumors arising from centrosome amplification exhibit frequent mitotic errors and possess complex karyotypes, recapitulating a common feature of human cancer. Together, our data support a direct causal relationship among centrosome amplification, genomic instability, and tumor development.
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Michelle S
authors.initials: MS
authors.lastname: Levine
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, the Netherlands.
authors.forename: Bjorn
authors.initials: B
authors.lastname: Bakker
authors.affiliation: Laboratory of Translational Genetics, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Translational Genetics, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Bram
authors.initials: B
authors.lastname: Boeckx
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Moyett
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: James
authors.initials: J
authors.lastname: Lu
authors.affiliation: CNRS UMR-5237, Centre de Recherche en Biochimie Macromoleculaire, University of Montpellier, Montpellier 34093, France.
authors.forename: Benjamin
authors.initials: B
authors.lastname: Vitre
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, the Netherlands.
authors.forename: Diana C
authors.initials: DC
authors.lastname: Spierings
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, the Netherlands.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Lansdorp
authors.affiliation: San Diego Branch, Ludwig Institute for Cancer Research, La Jolla, CA 92093, USA; Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, CA 92093, USA.
authors.forename: Don W
authors.initials: DW
authors.lastname: Cleveland
authors.affiliation: Laboratory of Translational Genetics, Vesalius Research Center, VIB, 3000 Leuven, Belgium; Laboratory of Translational Genetics, Department of Oncology, KU Leuven, 3000 Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: European Research Institute for the Biology of Ageing, University of Groningen, University Medical Center Groningen, Groningen 9713 AV, the Netherlands.
authors.forename: Floris
authors.initials: F
authors.lastname: Foijer
authors.affiliation: Department of Molecular Biology and Genetics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: aholland@jhmi.edu.
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Holland
mesh_terms: D000782:Aneuploidy; D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism* / Q000473:pathology*; D018385:Centrosome / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism; D007414:Intestinal Neoplasms / Q000473:pathology; D008322:Mammals / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D009928:Organ Specificity; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism
chemical_list: C088051:Plk4 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: Plk4; aneuploidy; centriole; centrosome amplification; genomic instability; mitosis; tumorigenesis