Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq

  • Biology
  • Cancer
  • Genomics
  • Medicine
  • Jay Prakadan
  • Marc Wadsworth
  • Alex Genshaft
  • Travis Hughes
  • Carly Ziegler
  • Sam Kazer
  • Aleth Gaillard
  • Kellie Kolb
  • Alex K. Shalek
  • Tirosh et al.▾
    Tirosh, I., Izar, B., Prakadan, S.M., Wadsworth II, M.H., Treacy, D., Trombetta, J.J., Rotem, A., Rodman, C., Lian, C., Murphy, G., Fallahi-Sichani, M., Dutton-Regester, K., Lin J., Cohen, O., Shah, P., Lu, D., Genshaft, A.S., Hughes, T.K., Ziegler, C.G.K., Kazer, S.W., Gaillard, A., Kolb, K.E., Villani, A., Johannessen, C.M., Andreev, A.Y., Van Allen, E.M., Bertagnolli, M., Sorger, P.K., Sullivan, R.J., Flaherty, K.T., Frederick, D.T., Jané-Valbuena, J., Yoon, C.H., Rozenblatt-Rosen, O., Shalek, A.K., Regev, A., Garraway, L.A.
  • Science , Volume 352
  • April, 2016
Biology
Cancer
Genomics
Medicine
Jay Prakadan
Marc Wadsworth
Alex Genshaft
Travis Hughes
Carly Ziegler
Sam Kazer
Aleth Gaillard
Kellie Kolb
Alex K. Shalek

Abstract

To explore the distinct genotypic and phenotypic states of melanoma tumors, we applied single-cell RNA sequencing (RNA-seq) to 4645 single cells isolated from 19 patients, profiling malignant, immune, stromal, and endothelial cells. Malignant cells within the same tumor displayed transcriptional heterogeneity associated with the cell cycle, spatial context, and a drug-resistance program. In particular, all tumors harbored malignant cells from two distinct transcriptional cell states, such that tumors characterized by high levels of the MITF transcription factor also contained cells with low MITF and elevated levels of the AXL kinase. Single-cell analyses suggested distinct tumor microenvironmental patterns, including cell-to-cell interactions. Analysis of tumor-infiltrating T cells revealed exhaustion programs, their connection to T cell activation and clonal expansion, and their variability across patients. Overall, we begin to unravel the cellular ecosystem of tumors and how single-cell genomics offers insights with implications for both targeted and immune therapies.

Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq