Abstract
Cancer metastasis is the most deadly stage in cancer progression. Despite significant efforts over the past decades, it remains elusive why only a very small fraction of cancer cells is able to generate micrometastasis and metastatic colonization. Recently we have shown that tumor-repopulating cells (TRCs), a highly tumorigenic subpopulation of mouse melanoma cells, can be selected by being cultured and grown in 3D soft fibrin gels. Here we show that when injected into the yolk of a 2 day-post-fertilization (dpf) embryo of Tg (fli1:EGFP or kdrl:mCherry) zebrafish, TRCs are much more efficient in surviving and growing at various secondary sites to generate micrometastasis and metastatic colonization than control melanoma cells that are grown on rigid plastic. The metastasis of TRCs is dependent on the presence of Sox2, a self-renewal gene, and silencing Sox2 leads to the inhibition of TRC metastasis. High-resolution of 3D confocal images of the TRCs at the secondary sites show that extravasation and formation of micrometastases by TRCs are more efficient than by the control cells. Remarkably, efficient extravasation of TRCs in vivo and transmigration in vitro are determined by TRC deformability, as a result of low Cdc42 and high Sox2. Our findings suggest that tumor cell deformability is a key factor in controlling extravasation dynamics during metastasis.
Highlights
Cancer metastasis is the most devastating stage of cancer[1]
Our current findings reveal that tumor-repopulating cells (TRCs), a small subpopulation of melanoma cells, exhibit higher proliferation, survival, and metastasis than their counterpart control melanoma cells in a zebrafish model
We find that low Cdc[42] and high deformability in Sox2-expressing TRCs are the underlying mechanisms of why these cells extravasate better than control cells, opposite from what would be predicted based on earlier findings on the roles of Cdc[42] in promoting tumor invasion[27,28]
Summary
Cancer metastasis is the most devastating stage of cancer[1]. Much efforts over the years have been devoted to understanding the process of metastasis[2,3,4,5,6,7,8,9,10,11] but the underlying mechanisms remain elusive. We recently have shown that a small subpopulation of melanoma tumor cells, selected from a general population of B16 melanoma cells and grown in a soft 3D fibrin matrix, are highly tumorigenic in culture and in syngeneic and nonsyngeneic immunocompetent mice[12,13]. These cells are defined as tumor-repopulating cells (TRCs)[13]. (b) Left panels: Representative images show that 500 tfRFP B16 cells were injected into the yolk sac (white arrow) of a zebrafish. Inset: yellow-dashed line rectangle box is the enlarged image of the small yellow box above; scale bar, 100 μ m
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