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

Cell. 2010 May 14;141(4):583-94. doi: 10.1016/j.cell.2010.04.020.

Abstract

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 exhaustion 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Calcium-Binding Proteins / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Gene Knockdown Techniques
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism
  • Jumonji Domain-Containing Histone Demethylases
  • Melanoma / metabolism*
  • Membrane Proteins / metabolism
  • Mice
  • Neoplasm Metastasis
  • Neoplastic Stem Cells / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Receptor, Notch1 / metabolism
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism*
  • Serrate-Jagged Proteins
  • Signal Transduction

Substances

  • Calcium-Binding Proteins
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins
  • NOTCH1 protein, human
  • Nuclear Proteins
  • Receptor, Notch1
  • Repressor Proteins
  • Serrate-Jagged Proteins
  • Jumonji Domain-Containing Histone Demethylases
  • KDM5B protein, human