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In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells
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In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells
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Journal Article
In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells
2015
Overview
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.
Publisher
Nature Publishing Group UK,Springer Nature B.V,Nature Publishing Group
Subject
/ 13/106
/ 14
/ 14/19
/ 14/35
/ 38
/ 38/61
/ 42
/ 42/44
/ Animals
/ Biomedical and Life Sciences
/ Cell Proliferation - physiology
/ Cellular Senescence - physiology
/ GTP Phosphohydrolases - metabolism
/ Humans
/ Membrane Proteins - metabolism
/ Mice
/ Neoplastic Stem Cells - metabolism
/ Neoplastic Stem Cells - pathology
/ Original
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