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A Temporarily Distinct Subpopulation# m) E$ l F# c. h, b5 q9 _9 `
of Slow-Cycling Melanoma Cells
P1 y$ ^: a0 k* w6 f( S4 VIs Required for Continuous Tumor Growth8 K: s+ H1 J* |+ `& J" D$ J X
9 K/ ^: g( m) [, k+ x! p# X
Melanomas are highly heterogeneous tumors, but the biological significance of their different subpopulations is not clear. Using the H3K4 demethylase JARID1B (KDM5B/PLU-1/RBP2-H1) as a biomarker, we have characterized a small subpopulation of slow-cycling melanoma cells that cycle with doubling times of >4 weeks within the rapidly proliferating main population. Isolated JARID1B-positive melanoma cells give rise to a highly proliferative progeny. Knockdown of JARID1B leads to an initial acceleration of tumor growth followed by exhaustion0 \' g. V- b; w( e: I* u
which suggests that the JARID1B-positive subpopulation is essential for continuous tumor growth. Expression of JARID1B is dynamically regulated and does not follow a hierarchical cancer stem cell model because JARID1B-negative cells can become positive and even single melanoma cells irrespective of selection are tumorigenic. These results suggest a new understanding of melanoma heterogeneity with tumor maintenance as a dynamic process mediated by a temporarily distinct subpopulation.8 p+ L$ p/ ^+ @, x
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