title: Transient PLK4 overexpression accelerates tumorigenesis in p53-deficient epidermis.
abstract: Aneuploidy is found in most solid tumours, but it remains unclear whether it is the cause or the consequence of tumorigenesis. Using Plk4 overexpression (PLK4OE) during epidermal development, we assess the impact of centrosome amplification and aneuploidy on skin development and tumorigenesis. PLK4OE in the developing epidermis induced centrosome amplification and multipolar divisions, leading to p53 stabilization and apoptosis of epidermal progenitors. The resulting delayed epidermal stratification led to skin barrier defects. Plk4 transgene expression was shut down postnatally in the surviving mice and PLK4OE mice never developed skin tumours. Concomitant PLK4OE and p53 deletion (PLK4OE/p53cKO) rescued the differentiation defects, but did not prevent the apoptosis of PLK4OE cells. Remarkably, the short-term presence of cells with supernumerary centrosomes in PLK4OE/p53cKO mice was sufficient to generate aneuploidy in the adult epidermis and triggered spontaneous skin cancers with complete penetrance. These results reveal that aneuploidy induced by transient centrosome amplification can accelerate tumorigenesis in p53-deficient cells.
authors.affiliation: Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
authors.forename: Özdemirhan
authors.initials: Ö
authors.lastname: Serçin
authors.affiliation: Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Larsimont
authors.affiliation: Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
authors.forename: Andrea E
authors.initials: AE
authors.lastname: Karambelas
authors.affiliation: Institut Curie, Centre de Recherche, Paris F-75248, France.
authors.forename: Veronique
authors.initials: V
authors.lastname: Marthiens
authors.affiliation: Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
authors.forename: Virginie
authors.initials: V
authors.lastname: Moers
authors.affiliation: Laboratory for Translational Genetics, Department of Oncology, KU Leuven 3000, Belgium.|Vesalius Research Center, VIB, 3000 Leuven, Belgium.
authors.forename: Bram
authors.initials: B
authors.lastname: Boeckx
authors.affiliation: Department of Pathology, Erasme Hospital, Université Libre de Bruxelles, Brussels B-1070, Belgium.
authors.forename: Marie
authors.initials: M
authors.lastname: Le Mercier
authors.affiliation: Laboratory for Translational Genetics, Department of Oncology, KU Leuven 3000, Belgium.|Vesalius Research Center, VIB, 3000 Leuven, Belgium.
authors.forename: Diether
authors.initials: D
authors.lastname: Lambrechts
authors.affiliation: Institut Curie, Centre de Recherche, Paris F-75248, France.
authors.forename: Renata
authors.initials: R
authors.lastname: Basto
authors.affiliation: Université Libre de Bruxelles, IRIBHM, Brussels B-1070, Belgium.
authors.forename: Cédric
authors.initials: C
authors.lastname: Blanpain
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D018385:Centrosome / Q000378:metabolism*; D004817:Epidermis / Q000378:metabolism*; D051379:Mice; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000235:genetics / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; C088051:Plk4 protein, mouse; D017346:Protein Serine-Threonine Kinases