Generation of highly tumorigenic cells from N-RAS61K-induced senescent cells

Activation of oncogene signaling in primary cells generally results in cellular senescence. This process is not only considered to be tumor-protective, but also irreversible. However, if senescence induction can be circumvented, e.g. by additional genetic or epigenetic changes, tumor progression occurs. An in-vivo example for oncogene-induced senescence are human nevus cells, most of which bear oncogenic mutations in RAS/RAF/MAPK pathway genes. Here, we show that expression of the human melanoma oncogene N-RAS61K in cultured pigment cells initially induces OIS characterized by a highly multinucleated phenotype. Surprisingly, after prolonged periods of oncogene expression, mononucleated cells emerge from the multinucleated cells. They are highly proliferative, anoikis-resistent and induce fast growing and metastatic melanoma upon transplantation into nude mice. During long-term oncogene expression and the corresponding development of anoikis iresistance, expression of melanocyte-specific genes is lost. Our data demonstrate that the induction of oncogene-induced senescence is not just a failsafe escape mechanism, but also provides a source for highly aggressive tumor cells.

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