Melanoma Stem Cells
The utility of different models to identify cancer stem cells continues to be a subject of intense debate.
Our long-term goal is to define the microenvironment within malignant lesions, i.e. matrix and stromal cells, that is responsible for self-renewal malignant cells and that likely also controls proliferation and invasion. Our initial studies studies were challenging because the melanoma stem cell population, as defined by us through either CD20, comprises only 0.1 to 1% of the total population.
Fang, D., Nguyen, T.K., Leishear, K., Finko, R., Kulp, A.N., Hotz, S., Van Belle, P.A., Xu, X., Elder, D.E., Herlyn, M.: A tumorigenic subpopulation with stem cell properties in melanomas. Cancer Res 65:9328-9337, 2005. PMID16230395
We have then characterized intra-tumoral heterogeneity of melanoma. Within a developing or already established tumor microenvironment, we propose that continuous tumor maintenance is assured by specific subpopulations whose phenotype is not static but instead is dynamically regulated. These small and temporarily distinct subpopulations likely play critical roles in tumor progression. They are important therapeutic targets but only in the context of combination therapies that also eliminate the bulk of the tumor. 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.
Roesch, A., Fukunaga-Kalabis, M., Schmidt, E.C., Zabierowski, S.E., Brafford, P.A., Vultur, A., Basu, D., Gimotty, P., Vogt, T., Herlyn, M.: A temporarily distinct subpopulation of slow-cycling melanoma cells is required for continuous tumor growth. Cell 141: 583-594, 2010. PMID204782552 (PMC2882693).
Fukunaga-Kalabis, M., Roesch, A., Herlyn, M.: From cancer stem cells to tumor maintainenance cells. J Invest. Dermatol. 131: 1600-1604, 2011. PMID 21654838
Characterization of sub-populations with stem cell-like properties