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

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

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 het...

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Bibliographic Details
Main Authors: Tirosh, I., Izar, B., Treacy, D., Trombetta, J. J., Rotem, A., Rodman, C., Lian, C., Murphy, G., Fallahi-Sichani, M., Dutton-Regester, K., Lin, J.-R., Cohen, O., Shah, P., Lu, D., Villani, A.-C., Andreev, A. Y., Van Allen, E. M., Bertagnolli, M., Sorger, P. K., Sullivan, R. J., Flaherty, K. T., Frederick, D. T., Jane-Valbuena, J., Rozenblatt-Rosen, O., Prakadan, Sanjay, Wadsworth, Marc Havens, Genshaft, Alex S., Hughes, Travis K., Ziegler, Carly, Kazer, Samuel Weisgurt, Gaillard de Saint Germain, Alethe, Kolb, Kellie Elizabeth, Johannessen, Cory M., Yoon, Clifford H., Shalek, Alexander K, Regev, Aviv, Garraway, Levi A.
Other Authors: Massachusetts Institute of Technology. Institute for Medical Engineering & Science
Format: Article
Language:en_US
Published: American Association for the Advancement of Science (AAAS) 2017
Online Access:http://hdl.handle.net/1721.1/110559
https://orcid.org/0000-0002-5621-8768
https://orcid.org/0000-0001-9376-164X
https://orcid.org/0000-0003-3079-5134
https://orcid.org/0000-0001-8291-8672
https://orcid.org/0000-0002-8279-7150
https://orcid.org/0000-0002-7380-9594
https://orcid.org/0000-0001-9179-7972
https://orcid.org/0000-0003-0710-7305
https://orcid.org/0000-0001-8567-2049
Description
Summary: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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