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Dissecting The Multicellular Ecosystem Of Metastatic Melanoma By Single-cell RNA-seq
I. Tirosh, Benjamin Izar, S. Prakadan, Marc H. Wadsworth, D. Treacy, John J. Trombetta, A. Rotem, C. Rodman, C. Lian, G. Murphy, M. Fallahi-Sichani, K. Dutton-Regester, Jia-Ren Lin, O. Cohen, Parin Shah, D. Lu, Alex S Genshaft, Travis K. Hughes, C. K. Ziegler, S. Kazer, Aleth Gaillard, Kellie E Kolb, A. Villani, Cory M. Johannessen, A. Andreev, E. V. Van Allen, M. Bertagnolli, P. Sorger, R. Sullivan, K. Flaherty, D. Frederick, Judit Jané-Valbuena, C. Yoon, O. Rozenblatt-Rosen, A. Shalek, A. Regev, L. Garraway
Published 2016 · Biology, Medicine
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Single-cell expression profiles of melanoma Tumors harbor multiple cell types that are thought to play a role in the development of resistance to drug treatments. Tirosh et al. used single-cell sequencing to investigate the distribution of these differing genetic profiles within melanomas. Many cells harbored heterogeneous genetic programs that reflected two different states of genetic expression, one of which was linked to resistance development. Following drug treatment, the resistance-linked expression state was found at a much higher level. Furthermore, the environment of the melanoma cells affected their gene expression programs. Science, this issue p. 189 Melanoma cells show transcriptional heterogeneity. 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.
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