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

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.

Identification of Melanoma Stem Cells in Long-term Cultures and of SOX6 as a Specific Biomarker for these Stem Cells

“…It has also been suggested that these characteristics of melanoma are correlated with the presence of a subpopulation of tumor-initiating cells called cancer stem cells. Recent studies have identified a subpopulation with the same characteristics of stem cells in human cancer and fresh tumors [38,39].…”

Biomarkers to identify and isolate senescent cells

“…These accumulating senescent cells can (iii) damage surrounding cells (Biran and Krizhanovsky, 2015) and cause (iv) cancer (Leikam et al, 2015) and (v) other agerelated diseases, such as atherosclerosis (Erusalimsky and Kurz, 2005;Fischer et al, 2013;Nishimatsu et al, 2015). Although senescent cells play an important role in (vi) tumor suppression (Tominaga, 2015), (vii) wound healing (Demaria et al, 2014) and development, (viii) periodically removing them does not produce significant side-effects .…”

“…However, accumulation of senescent cells in tissues is detrimental to the animal (Herbig et al, 2006;Jeyapalan et al, 2007) as these non-functional cells directly and indirectly damage surrounding cells (Salama et al, 2014). Examples of such damage include occupying niches required by competent cells to function , secreting transforming, inflammatory and otherwise damaging components of the SASP (Campisi and d'Adda di Fagagna, 2007;Coppé et al, , 2008, promoting tumour formation (Leikam et al, 2015;Zacarias-Fluck et al, 2015) and contributing to various age-related diseases such as atherosclerosis (Irvine et al, 2014;Wang and Bennett, 2012).…”

Linking genomic reorganization to tumor initiation via the giant cell cycle

“…16, 17, 18 Regrowth from giant cells via de-polyploidization terminated by budding of the daughter cells has been observed in senescent fibroblasts 19 and in cancer cells after radiation therapy, 20, 21 chemotherapy 22, 23, 24, 25, 26 and RAS oncogene activation. 27 Polyploidy can facilitate senescence-induced replication barrier and promote tumor progression. 28 Whole-genomic doubling has been shown to accelerate cancer genomic evolution.…”