title: A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth.
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.
authors.affiliation: The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Roesch
authors.forename: Mizuho
authors.initials: M
authors.lastname: Fukunaga-Kalabis
authors.forename: Elizabeth C
authors.initials: EC
authors.lastname: Schmidt
authors.forename: Susan E
authors.initials: SE
authors.lastname: Zabierowski
authors.forename: Patricia A
authors.initials: PA
authors.lastname: Brafford
authors.forename: Adina
authors.initials: A
authors.lastname: Vultur
authors.forename: Devraj
authors.initials: D
authors.lastname: Basu
authors.forename: Phyllis
authors.initials: P
authors.lastname: Gimotty
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogt
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
mesh_terms: 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
chemical_list: 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