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.
Highlights
Along the same lines, oncogenic RAS clearly triggers oncogene-induced senescence (OIS) in different cell types in vivo,[3,4,5,6] but activated RAS is detected in up to 30% of human cancers.[7,8] This indicates that senescence bypass is a key feature of cancer development
The causes leading to multinucleation can be manifold and encompass UV damage, elevated levels of reactive oxygen species (ROS) and oncogenic stress, for example, by the melanoma oncogene N-RAS61K that efficiently induces OIS in melanocytes.[11,12,14,15]
OIS is widely considered to be a tumor-suppressive process, we found that cultivation of oncogene-expressing primary human melanocytes for more than 3 weeks led to the generation of proliferating cell clones (Figures 1d and e)
Summary
Oncogenic RAS clearly triggers OIS in different cell types in vivo,[3,4,5,6] but activated RAS is detected in up to 30% of human cancers.[7,8] This indicates that senescence bypass is a key feature of cancer development. We reveal that long-term NRAS61K activation in melanocytes triggers a strong senescent phenotype characterized by multinucleation, which is followed by the post-senescence generation of tumor-initiating cells with stem cell-like properties. The results demonstrate that senescence in melanocytes can be overcome on the cellular level and can be a source for malignant cancer cells
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