Metastatic potential in clonal melanoma cells is driven by a rare, early-invading subpopulation

Metastasis occurs when tumor cells leave the primary tumor site and disseminate to distal organs. Most cells remain in the primary tumor, however, the circumstances that allow certain cells to drive this dissemination remain unclear. Here, we show that rare, highly invasive melanoma cells can appear even within clonal cell lines due to non-genetic fluctuations. These differences were intrinsic to the cells independent of their external context, and were marked by transiently high levels of SEMA3C expression. The invasive subpopulation drove dissemination of tumor cells to distal locations in a mouse model of melanoma. The transcription factor NKX2.2 emerged as a regulator of the proportion of invasive cells. There was an overall tradeoff between proliferation and invasion in single cells. Our results suggest that phenotypes like metastasis can be the result of intrinsic differences between single cells. ### Competing Interest Statement AR receives royalties related to Stellaris RNA FISH probes. All other authors declare no competing interests.