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

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 irreversibl...

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Main 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, Meierjohann, S
Format:	Online
Language:	English
Published:	Nature Publishing Group 2015
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650540/

id	pubmed-4650540
recordtype	oai_dc
spelling	pubmed-46505402015-12-01 In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells 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 Meierjohann, S Original Article 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. Nature Publishing Group 2015-04 2015-04-02 /pmc/articles/PMC4650540/ /pubmed/25837487 http://dx.doi.org/10.1038/cddis.2015.71 Text en Copyright © 2015 Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ Cell Death and Disease is an open-access journal published by Nature Publishing Group. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	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 Meierjohann, S
spellingShingle	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 Meierjohann, S In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells
author_facet	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 Meierjohann, S
author_sort	Leikam, C
title	In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells
title_short	In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells
title_full	In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells
title_fullStr	In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells
title_full_unstemmed	In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells
title_sort	in vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells
description	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.
publisher	Nature Publishing Group
publishDate	2015
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4650540/
_version_	1613503120431644672

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

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