Abstract Metastasis occurs when tumor cells leave the primary tumor site and disseminate to distal organs. Even though most cells remain in the primary tumor, the circumstances by which a small fraction of them disseminate remain unclear. Here, we show that a rare, highly invasive subpopulation of melanoma cells can be detected within clonal cell lines due to non-genetic fluctuations in gene expression. The highly invasive phenotype was intrinsic to the cells, independent of their environment, and was marked by transiently high levels of SEMA3C expression, as revealed by RNA-sequencing analysis. Furthermore, the invasive subpopulation drove the bulk dissemination of tumor cells to distal locations in a mouse model of melanoma. The transcription factor NKX2.2 regulated the proportion of invasive cells in the melanoma 1205Lu cell line. Furthermore, an overall tradeoff between proliferation and invasion in single cells was observed. Our results suggest that phenotypes like metastasis may arise from intrinsic differences stemming from non-genetic fluctuations between single cells.

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