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

• Main Authors: Tirosh, I. (Author), Izar, B. (Author), Treacy, D. (Author), Trombetta, J. J. (Author), Rotem, A. (Author), Rodman, C. (Author), Lian, C. (Author), Murphy, G. (Author), Fallahi-Sichani, M. (Author), Dutton-Regester, K. (Author), Lin, J.-R (Author), Cohen, O. (Author), Shah, P. (Author), Lu, D. (Author), Villani, A.-C (Author), Andreev, A. Y. (Author), Van Allen, E. M. (Author), Bertagnolli, M. (Author), Sorger, P. K. (Author), Sullivan, R. J. (Author), Flaherty, K. T. (Author), Frederick, D. T. (Author), Jane-Valbuena, J. (Author), Rozenblatt-Rosen, O. (Author), Prakadan, Sanjay (Contributor), Wadsworth, Marc Havens (Contributor), Genshaft, Alex S. (Contributor), Hughes, Travis K. (Contributor), Ziegler, Carly (Contributor), Kazer, Samuel Weisgurt (Contributor), Gaillard de Saint Germain, Alethe (Contributor), Kolb, Kellie Elizabeth (Contributor), Johannessen, Cory M. (Contributor), Yoon, Clifford H. (Contributor), Shalek, Alexander K (Contributor), Regev, Aviv (Contributor), Garraway, Levi A. (Author)
• Other Authors: Massachusetts Institute of Technology. Institute for Medical Engineering & Science (Contributor), Broad Institute of MIT and Harvard (Contributor), Massachusetts Institute of Technology. Department of Chemistry (Contributor), Garraway, Levi (Contributor)
• Format: Article
• Language: English
• Published: American Association for the Advancement of Science (AAAS), 2017-07-07T19:22:03Z.
• Subjects: Article
• Online Access: Get fulltext

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.
National Cancer Institute (U.S.) (1U24CA180922)
National Cancer Institute (U.S.) (P30-CA14051)