Circulating Melanoma Cell Subpopulations: Their Heterogeneity and Differential Responses to Treatment

J Invest Dermatol. 2015 Aug;135(8):2040-2048. doi: 10.1038/jid.2015.127. Epub 2015 Apr 1.


Metastatic melanoma is a highly heterogeneous tumor; thus, methods to analyze tumor-derived cells circulating in blood should address this diversity. Taking this into account, we analyzed, using multiparametric flow cytometry, the co-expression of the melanoma markers melanoma cell adhesion molecule and melanoma-associated chondroitin sulphate proteoglycan and the tumor-initiating markers ATP-binding cassette sub-family B member 5 (ABCB5), CD271, and receptor activator of NF-κβ (RANK) in individual circulating tumor cells (CTCs) from 40 late-stage (III-IV) and 16 early-stage (I-II) melanoma patients. CTCs were heterogeneous within and between patients, with limited co-expression between the five markers analyzed. Analysis of patient matched blood and metastatic tumors revealed that ABCB5 and RANK subpopulations are more common among CTCs than in the solid tumors, suggesting a preferential selection for these cells in circulation. Pairwise comparison of CTC subpopulations longitudinally before and 6-13 weeks after treatment initiation showed that the percentage of RANK(+) CTCs significantly increased in the patients undergoing targeted therapy (N=16, P<0.01). Moreover, the presence of ⩾5 RANK(+) CTCs in the blood of patients undergoing targeted therapies was prognostic of shorter progression-free survival (hazards ratio 8.73, 95% confidence interval 1.82-41.75, P<0.01). Taken together, our results provide evidence of the heterogeneity among CTC subpopulations in melanoma and the differential response of these subpopulations to targeted therapy.

Publication types

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

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1 / metabolism
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / metabolism*
  • CD146 Antigen / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Chondroitin Sulfate Proteoglycans / metabolism
  • Drug Therapy
  • Female
  • Humans
  • Immunotherapy
  • Indoles / pharmacology
  • Indoles / therapeutic use
  • Male
  • Melanoma / drug therapy*
  • Melanoma / metabolism*
  • Melanoma / pathology
  • Membrane Proteins / metabolism
  • Middle Aged
  • Neoplasm Staging
  • Neoplastic Cells, Circulating / drug effects*
  • Neoplastic Cells, Circulating / metabolism*
  • Neoplastic Cells, Circulating / pathology
  • Nerve Tissue Proteins / metabolism
  • Receptor Activator of Nuclear Factor-kappa B / metabolism
  • Receptors, Nerve Growth Factor / metabolism
  • Skin Neoplasms / drug therapy*
  • Skin Neoplasms / metabolism*
  • Skin Neoplasms / pathology
  • Sulfonamides / pharmacology
  • Sulfonamides / therapeutic use
  • Vemurafenib


  • ABCB5 protein, human
  • ATP Binding Cassette Transporter, Subfamily B
  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Biomarkers, Tumor
  • CD146 Antigen
  • CSPG4 protein, human
  • Chondroitin Sulfate Proteoglycans
  • Indoles
  • Membrane Proteins
  • NGFR protein, human
  • Nerve Tissue Proteins
  • Receptor Activator of Nuclear Factor-kappa B
  • Receptors, Nerve Growth Factor
  • Sulfonamides
  • TNFRSF11A protein, human
  • Vemurafenib