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

Itay Tirosh, Benjamin Izar, Sanjay M. Prakadan, Marc H. Wadsworth, Daniel Treacy, John J. Trombetta, Asaf Rotem, Christopher Rodman, Christine Lian, George Murphy, Mohammad Fallahi-Sichani, Ken Dutton-Regester, Jia Ren Lin, Ofir Cohen, Parin Shah, Diana Lu, Alex S. Genshaft, Travis K. Hughes, Carly G.K. Ziegler, Samuel W. KazerAleth Gaillard, Kellie E. Kolb, Alexandra Chloé Villani, Cory M. Johannessen, Aleksandr Y. Andreev, Eliezer M. Van Allen, Monica Bertagnolli, Peter K. Sorger, Ryan J. Sullivan, Keith T. Flaherty, Dennie T. Frederick, Judit Jané-Valbuena, Charles H. Yoon, Orit Rozenblatt-Rosen, Alex K. Shalek, Aviv Regev, Levi A. Garraway

Research output: Contribution to journalArticlepeer-review


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 Tcell 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.

Original languageEnglish
Pages (from-to)189-196
Number of pages8
Issue number6282
StatePublished - 8 Apr 2016
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • General


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