BRAF and MEK inhibitor therapy eliminates Nestin-expressing melanoma cells in human tumors.

Doxie DB, Greenplate AR, Gandelman JS, Diggins KE, Roe CE, Dahlman KB, Sosman JA, Kelley MC, Irish JM
Pigment Cell Melanoma Res. 2018 31 (6): 708-719

PMID: 29778085 · PMCID: PMC6188784 · DOI:10.1111/pcmr.12712

Little is known about the in vivo impacts of targeted therapy on melanoma cell abundance and protein expression. Here, 21 antibodies were added to an established melanoma mass cytometry panel to measure 32 cellular features, distinguish malignant cells, and characterize dabrafenib and trametinib responses in BRAF melanoma. Tumor cells were biopsied before neoadjuvant therapy and compared to cells surgically resected from the same site after 4 weeks of therapy. Approximately 50,000 cells per tumor were characterized by mass cytometry and computational tools t-SNE/viSNE, FlowSOM, and MEM. The resulting single-cell view of melanoma treatment response revealed initially heterogeneous melanoma tumors were consistently cleared of Nestin-expressing melanoma cells. Melanoma cell subsets that persisted to week 4 were heterogeneous but expressed SOX2 or SOX10 proteins and specifically lacked surface expression of MHC I proteins by MEM analysis. Traditional histology imaging of tissue microarrays from the same tumors confirmed mass cytometry results, including persistence of NES- SOX10+ S100β+ melanoma cells. This quantitative single-cell view of melanoma treatment response revealed protein features of malignant cells that are not eliminated by targeted therapy.

© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

MeSH Terms (13)

Antibodies, Neoplasm Cell Line, Tumor Humans Imidazoles Melanoma Mitogen-Activated Protein Kinase Kinases Nestin Oximes Phenotype Protein Kinase Inhibitors Proto-Oncogene Proteins B-raf Pyridones Pyrimidinones

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