TY  - JOUR
A1  - Leikam, C
A1  - Hufnagel, AL
A1  - Otto, C
A1  - Murphy, DJ
A1  - Mühling, B
A1  - Kneitz, S
A1  - Nanda, I
A1  - Schmid, M
A1  - Wagner, TU
A1  - Haferkamp, S
A1  - Bröcker, E-B
A1  - Schartl, M
A1  - Meierjohann, S
T1  - In vitro evidence for senescent multinucleated melanocytes as a source for tumor-initiating cells
JF  - Cell Death and Disease
N2  - 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.
KW  - reactive oxygen
KW  - human melanoma
KW  - MITF
KW  - cancer
KW  - skin
KW  - DNA damage
KW  - kappa-B
KW  - oncogene-induced senescence
KW  - cellular senescence
Y1  - 2015
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-148718
VL  - 6
IS  - e1711
ER  -