A Temporarily Distinct Subpopulation of Slow-Cycling Melanoma Cells Is Required for Continuous Tumor Growth

摘要

Melanomas are highly heterogeneous tumors, but the biological significance of their different subpopu-lations is not clear. Using the H3K4 demethylase JARID1 B (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 JARID1 B-positive melanoma cells give rise to a highly proliferative progeny. Knockdown of JARID1 B leads to an initial acceleration of tumor growth followed by exhaustion which suggests that the JARID1 B-positive subpopulation is essential for continuous tumor growth. Expression of JARID1 B is dynamically regulated and does not follow a hierarchical cancer stem cell model because JARID1 B-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.