A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth.
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.
Roesch
Alexander
A
The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
Fukunaga-Kalabis
Mizuho
M
Schmidt
Elizabeth C
EC
Zabierowski
Susan E
SE
Brafford
Patricia A
PA
Vultur
Adina
A
Basu
Devraj
D
Gimotty
Phyllis
P
Vogt
Thomas
T
Herlyn
Meenhard
M
D000818:Animals; D002135:Calcium-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D055785:Gene Knockdown Techniques; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D056484:Jumonji Domain-Containing Histone Demethylases; D008545:Melanoma / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis; D014411:Neoplastic Stem Cells / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction
D002135:Calcium-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; D009687:Nuclear Proteins; D051881:Receptor, Notch1; D012097:Repressor Proteins; D000072099:Serrate-Jagged Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human