A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth

By A. Roesch, M. Fukunaga-Kalabis, E. C. Schmidt, S. Zabierowski, Patricia Brafford, A. Vultur, D. Basu, P. Gimotty, T. Vogt, Meenhard Herlyn. Cell, 2010

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Summary 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. Knock-down 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.

Subfields: Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/541ae15ee24297c76789c4c7dd1bcbc3701269d1

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Citations in the corpus

Cancer stem cells: impact, heterogeneity, and uncertainty. (2012, background): “The idea that cancer cells might reversibly transition between epigenetically defined tumorigenic and nontumorigenic states is appealing, partly because mechanisms that generate reversible heterogeneity can confer therapy resistance (Roesch et al., 2010; Sharma et al., 2010).”
The Cancer Stem Cell Niche: How Essential is the Niche in Regulating Stemness of Tumor Cells? (2015, neutral): “Dormancy is a critical issue for tumor recurrence and metastatic spread after long lag periods in many cancers, including breast, melanoma, and leukemia (Pece et al., 2010; Roesch et al., 2010; Saito et al., 2010).”
Poised chromatin at the ZEB1 promoter enables cell plasticity and enhances tumorigenicity (2013, neutral): “We and others have recently demonstrated that nonCSCs can acquire CSC-like activity under certain conditions (Chaffer et al., 2011; Gupta et al., 2011; Roesch et al., 2010).”
Overcoming intrinsic multi-drug resistance in melanoma by blocking the mitochondrial respiratory chain of slow-cycling JARID1Bhigh cells (2013, methodology): “Here, a significant reduction in colony growth was seen after 3 weeks of treatment (Figure 6F, right panel), which is reminiscent of the results previously reported for JARID1B knockdown (Roesch et al., 2010).”
Reconstructing and reprogramming the tumor propagating potential of glioblastoma stem-like cells (2014, background): “For example, recent studies indicate that stem-like cells in breast cancer and melanoma exist in dynamic equilibrium with phenotypically distinct populations incapable of tumor propagation (Chaffer et al., 2013; Roesch et al., 2010).”
Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq (2016, positive): “KDM5B-expressing cells were grouped in small clusters, consistent with observations in mouse and in vitro models (21) (Figs.”
Evolution of the cancer stem cell model. (2014, background): “JARID1B was shown to mark slowly cycling melanoma cells that are essential for continuous tumor growth of established melanomas and metastatic progression, but are not required for tumor initiation (Roesch et al., 2010).”
Phenotypic heterogeneity among tumorigenic melanoma cells from patients that is reversible and not hierarchically organized (2010, background): “The JARID1B histone demethylase regulates the tumorigenic activity of melanoma cell lines and can also reversibly turn on and off, raising the possibility that competence to form a tumor is reversible (Roesch et al., 2010).”