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In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells

Please always quote using this URN: urn:nbn:de:bvb:20-opus-148718
  • 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 cellsOncogenic 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.show moreshow less

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Metadaten
Author: C Leikam, AL Hufnagel, C Otto, DJ Murphy, B Mühling, S Kneitz, I Nanda, M Schmid, TU Wagner, S Haferkamp, E-B Bröcker, M Schartl, S Meierjohann
URN:urn:nbn:de:bvb:20-opus-148718
Document Type:Journal article
Faculties:Medizinische Fakultät / Klinik und Poliklinik für Allgemein-, Viszeral-, Gefäß- und Kinderchirurgie (Chirurgische Klinik I)
Medizinische Fakultät / Theodor-Boveri-Institut für Biowissenschaften
Language:English
Parent Title (English):Cell Death and Disease
Year of Completion:2015
Volume:6
Issue:e1711
Source:Cell Death and Disease (2015) 6, e1711. DOI: 10.1038/cddis.2015.71
DOI:https://doi.org/10.1038/cddis.2015.71
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Tag:DNA damage; MITF; cancer; cellular senescence; human melanoma; kappa-B; oncogene-induced senescence; reactive oxygen; skin
Release Date:2018/11/21
Licence (German):License LogoCC BY: Creative-Commons-Lizenz: Namensnennung 4.0 International