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

Leikam, C. et al. (2015) In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells. Cell Death and Disease, 6(4), e1711. (doi: 10.1038/cddis.2015.71) (PMID:25837487)

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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-RAS61K 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.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Murphy, Professor Daniel
Authors: Leikam, C., Hufnagel, A.L., Otto, C., Murphy, D.J., Mühling, B., Kneitz, S., Nanda, I., Schmid, M., Wagner, T.U., Haferkamp, S., Bröcker, E.-B., Schartl, M., and Meierjohann, S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Journal Name:Cell Death and Disease
Publisher:Nature Publishing Group
ISSN:2041-4889
ISSN (Online):2041-4889
Copyright Holders:Copyright © 2015 The Authors
First Published:First published in Cell Death and Disease 6(4):e1711
Publisher Policy:Reproduced under a Creative Commons License

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