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

Biology Biology
Cancer Cancer
Genomics Genomics
Medicine Medicine
Aleth Gaillard Aleth Gaillard
Alex Genshaft Alex Genshaft
Alex K. Shalek Alex K. Shalek
Carly Ziegler Carly Ziegler
Jay Prakadan Jay Prakadan
Kellie Kolb Kellie Kolb
Marc Wadsworth II Marc Wadsworth II
Sam Kazer Sam Kazer
Travis Hughes Travis Hughes

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


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.