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Science DOI:10.1126/science.aad0501

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

Publication TypeJournal Article
Year of Publication2016
AuthorsTirosh, I, Izar, B, Prakadan, SM, Wadsworth, MH, Treacy, D, Trombetta, JJ, Rotem, A, Rodman, C, Lian, C, Murphy, G, Fallahi-Sichani, M, Dutton-Regester, K, Lin, J-R, Cohen, O, Shah, P, Lu, D, Genshaft, AS, Hughes, TK, Ziegler, CGK, Kazer, SW, Gaillard, A, Kolb, KE, Villani, A-C, Johannessen, CM, Andreev, AY, Van Allen, EM, Bertagnolli, M, Sorger, PK, Sullivan, RJ, Flaherty, KT, Frederick, DT, Jané-Valbuena, J, Yoon, CH, Rozenblatt-Rosen, O, Shalek, AK, Regev, A, Garraway, LA
JournalScience
Volume352
Issue6282
Pages189-96
Date Published2016 Apr 08
ISSN1095-9203
KeywordsBase Sequence, Cell Communication, Cell Cycle, Drug Resistance, Neoplasm, Endothelial Cells, Genomics, Humans, Immunotherapy, Lymphocyte Activation, Melanoma, Microphthalmia-Associated Transcription Factor, Neoplasm Metastasis, RNA, Sequence Analysis, RNA, Single-Cell Analysis, Skin Neoplasms, Stromal Cells, T-Lymphocytes, Transcriptome, Tumor Microenvironment
Abstract

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.

URLhttp://www.sciencemag.org/cgi/pmidlookup?view=long&pmid=27124452
DOI10.1126/science.aad0501
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/27124452?dopt=Abstract

Alternate JournalScience
PubMed ID27124452
PubMed Central IDPMC4944528
Grant ListU24 CA180922 / CA / NCI NIH HHS / United States
K99 CA194163 / CA / NCI NIH HHS / United States
P50GM107618 / GM / NIGMS NIH HHS / United States
P50 GM107618 / GM / NIGMS NIH HHS / United States
P01 CA163222 / CA / NCI NIH HHS / United States
P30 CA014051 / CA / NCI NIH HHS / United States
P30-CA14051 / CA / NCI NIH HHS / United States
DP2 GM119419 / GM / NIGMS NIH HHS / United States
U54CA112962 / CA / NCI NIH HHS / United States
R35CA197737 / CA / NCI NIH HHS / United States
P01CA163222 / CA / NCI NIH HHS / United States
R35 CA197737 / CA / NCI NIH HHS / United States
R33 CA202820 / CA / NCI NIH HHS / United States
K99CA194163 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States
U54 CA112962 / CA / NCI NIH HHS / United States
DP2 OD020839 / OD / NIH HHS / United States
1U24CA180922 / CA / NCI NIH HHS / United States