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

Deon B. Doxie, Allison R. Greenplate, Jocelyn S. Gandelman, Kirsten E. Diggins, Caroline E. Roe, Kimberly B. Dahlman, Jeffrey A. Sosman, Mark C. Kelley, Jonathan M. Irish*

*Corresponding author for this work

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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 V600mut 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.

Original languageEnglish (US)
Pages (from-to)708-719
Number of pages12
JournalPigment Cell and Melanoma Research
Volume31
Issue number6
DOIs
StatePublished - Nov 2018

Keywords

  • kinase inhibitors
  • mass cytometry
  • melanoma
  • single cell
  • targeted therapy

ASJC Scopus subject areas

  • Oncology
  • Biochemistry, Genetics and Molecular Biology(all)
  • Dermatology

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    Doxie, D. B., Greenplate, A. R., Gandelman, J. S., Diggins, K. E., Roe, C. E., Dahlman, K. B., Sosman, J. A., Kelley, M. C., & Irish, J. M. (2018). BRAF and MEK inhibitor therapy eliminates Nestin-expressing melanoma cells in human tumors. Pigment Cell and Melanoma Research, 31(6), 708-719. https://doi.org/10.1111/pcmr.12712