title: In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells.
abstract: Oncogenic signaling in melanocytes results in oncogene-induced senescence (OIS), a stable cell-cycle arrest frequently characterized by a bi- or multinuclear phenotype that is considered as a barrier to cancer progression. However, the long-sustained conviction that senescence is a truly irreversible process has recently been challenged. Still, it is not known whether cells driven into OIS can progress to cancer and thereby pose a potential threat. Here, we show that prolonged expression of the melanoma oncogene N-RAS(61K) in pigment cells overcomes OIS by triggering the emergence of tumor-initiating mononucleated stem-like cells from senescent cells. This progeny is dedifferentiated, highly proliferative, anoikis-resistant and induces fast growing, metastatic tumors. Our data describe that differentiated cells, which are driven into senescence by an oncogene, use this senescence state as trigger for tumor transformation, giving rise to highly aggressive tumor-initiating cells. These observations provide the first experimental in vitro evidence for the evasion of OIS on the cellular level and ensuing transformation.
authors.affiliation: Department of Physiological Chemistry I, University of Wurzburg, Biocenter, Am Hubland, Wurzburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Leikam
authors.affiliation: Department of Physiological Chemistry I, University of Wurzburg, Biocenter, Am Hubland, Wurzburg, Germany.
authors.forename: A L
authors.initials: AL
authors.lastname: Hufnagel
authors.affiliation: Experimental Surgery, Experimental Transplantation Immunology, Clinic of General, Visceral, Vascular and Pediatric Surgery (Surgical Clinic I), University of Wurzburg Hospital, Wurzburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Otto
authors.affiliation: Institute of Cancer Sciences, Beatson Institute for Cancer Research, University of Glasgow, Glasglow, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Murphy
authors.affiliation: Experimental Surgery, Experimental Transplantation Immunology, Clinic of General, Visceral, Vascular and Pediatric Surgery (Surgical Clinic I), University of Wurzburg Hospital, Wurzburg, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Mühling
authors.affiliation: Department of Physiological Chemistry I, University of Wurzburg, Biocenter, Am Hubland, Wurzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Kneitz
authors.affiliation: Institute for Human Genetics, University of Wurzburg, Biocenter, Am Hubland, Wurzburg, Germany.
authors.forename: I
authors.initials: I
authors.lastname: Nanda
authors.affiliation: Institute for Human Genetics, University of Wurzburg, Biocenter, Am Hubland, Wurzburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schmid
authors.affiliation: Department of Physiological Chemistry I, University of Wurzburg, Biocenter, Am Hubland, Wurzburg, Germany.
authors.forename: T U
authors.initials: TU
authors.lastname: Wagner
authors.affiliation: Department of Dermatology, University Hospital Erlangen, Erlangen, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Haferkamp
authors.affiliation: Department of Dermatology, Venereology and Allergology, University Hospital Wurzburg, Wurzburg, Germany.
authors.forename: E-B
authors.initials: EB
authors.lastname: Bröcker
authors.affiliation: 1] Department of Physiological Chemistry I, University of Wurzburg, Biocenter, Am Hubland, Wurzburg, Germany [2] Comprehensive Cancer Center Mainfranken, University Hospital Wurzburg, Wurzburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schartl
authors.affiliation: 1] Department of Physiological Chemistry I, University of Wurzburg, Biocenter, Am Hubland, Wurzburg, Germany [2] Comprehensive Cancer Center Mainfranken, University Hospital Wurzburg, Wurzburg, Germany.
authors.forename: S
authors.initials: S
authors.lastname: Meierjohann
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D016922:Cellular Senescence / Q000502:physiology; D020558:GTP Phosphohydrolases / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D066298:In Vitro Techniques; D008544:Melanocytes / Q000378:metabolism / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D009506:Nevus / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction
chemical_list: D008565:Membrane Proteins; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
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