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

Itay Tirosh; Benjamin Izar; Sanjay M. Prakadan; Marc H. Wadsworth; Daniel Treacy; John J. Trombetta; Asaf Rotem; Christopher Rodman; Christine Lian; George Murphy; Mohammad Fallahi-Sichani; Ken Dutton-Regester; Jia Ren Lin; Ofir Cohen; Parin Shah; Diana Lu; Alex S. Genshaft; Travis K. Hughes; Carly G.K. Ziegler; Samuel W. Kazer; Aleth Gaillard; Kellie E. Kolb; Alexandra Chloé Villani; Cory M. Johannessen; Aleksandr Y. Andreev; Eliezer M. Van Allen; Monica Bertagnolli; Peter K. Sorger; Ryan J. Sullivan; Keith T. Flaherty; Dennie T. Frederick; Judit Jané-Valbuena; Charles H. Yoon; Orit Rozenblatt-Rosen; Alex K. Shalek; Aviv Regev; Levi A. Garraway

doi:https://doi.org/10.1126/science.aad0501

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

Itay Tirosh, Benjamin Izar, Sanjay M. Prakadan, Marc H. Wadsworth, Daniel Treacy, John J. Trombetta, Asaf Rotem, Christopher Rodman, Christine Lian, George Murphy, Mohammad Fallahi-Sichani, Ken Dutton-Regester, Jia Ren Lin, Ofir Cohen, Parin Shah, Diana Lu, Alex S. Genshaft, Travis K. Hughes, Carly G.K. Ziegler, Samuel W. KazerAleth Gaillard, Kellie E. Kolb, Alexandra Chloé Villani, Cory M. Johannessen, Aleksandr Y. Andreev, Eliezer M. Van Allen, Monica Bertagnolli, Peter K. Sorger, Ryan J. Sullivan, Keith T. Flaherty, Dennie T. Frederick, Judit Jané-Valbuena, Charles H. Yoon, Orit Rozenblatt-Rosen, Alex K. Shalek, Aviv Regev, Levi A. Garraway

Research output: Contribution to journal › Article › peer-review

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 Tcell 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.

Original language	American English
Pages (from-to)	189-196
Number of pages	8
Journal	Science
Volume	352
Issue number	6282
DOIs	https://doi.org/10.1126/science.aad0501
State	Published - 8 Apr 2016
Externally published	Yes

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This output contributes to the following UN Sustainable Development Goals (SDGs)

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Tirosh, I., Izar, B., Prakadan, S. M., Wadsworth, M. H., 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., Genshaft, A. S., Hughes, T. K., Ziegler, C. G. K., ... Garraway, L. A. (2016). Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq. Science, 352(6282), 189-196. https://doi.org/10.1126/science.aad0501

@article{4c85ef0c387d41c6b6c343f86a117e5f,

title = "Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq",

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 Tcell 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.",

author = "Itay Tirosh and Benjamin Izar and Prakadan, {Sanjay M.} and Wadsworth, {Marc H.} and Daniel Treacy and Trombetta, {John J.} and Asaf Rotem and Christopher Rodman and Christine Lian and George Murphy and Mohammad Fallahi-Sichani and Ken Dutton-Regester and Lin, {Jia Ren} and Ofir Cohen and Parin Shah and Diana Lu and Genshaft, {Alex S.} and Hughes, {Travis K.} and Ziegler, {Carly G.K.} and Kazer, {Samuel W.} and Aleth Gaillard and Kolb, {Kellie E.} and Villani, {Alexandra Chlo{\'e}} and Johannessen, {Cory M.} and Andreev, {Aleksandr Y.} and {Van Allen}, {Eliezer M.} and Monica Bertagnolli and Sorger, {Peter K.} and Sullivan, {Ryan J.} and Flaherty, {Keith T.} and Frederick, {Dennie T.} and Judit Jan{\'e}-Valbuena and Yoon, {Charles H.} and Orit Rozenblatt-Rosen and Shalek, {Alex K.} and Aviv Regev and Garraway, {Levi A.}",

year = "2016",

month = apr,

day = "8",

doi = "https://doi.org/10.1126/science.aad0501",

language = "American English",

volume = "352",

pages = "189--196",

journal = "Science",

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publisher = "American Association for the Advancement of Science",

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Tirosh, 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, JR, Cohen, O, Shah, P, Lu, D, Genshaft, AS, Hughes, TK, Ziegler, CGK, Kazer, SW, Gaillard, A, Kolb, KE, Villani, AC, 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 2016, 'Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq', Science, vol. 352, no. 6282, pp. 189-196. https://doi.org/10.1126/science.aad0501

TY - JOUR

T1 - Dissecting the multicellular ecosystem of metastatic melanoma by single-cell RNA-seq

AU - Tirosh, Itay

AU - Izar, Benjamin

AU - Prakadan, Sanjay M.

AU - Wadsworth, Marc H.

AU - Treacy, Daniel

AU - Trombetta, John J.

AU - Rotem, Asaf

AU - Rodman, Christopher

AU - Lian, Christine

AU - Murphy, George

AU - Fallahi-Sichani, Mohammad

AU - Dutton-Regester, Ken

AU - Lin, Jia Ren

AU - Cohen, Ofir

AU - Shah, Parin

AU - Lu, Diana

AU - Genshaft, Alex S.

AU - Hughes, Travis K.

AU - Ziegler, Carly G.K.

AU - Kazer, Samuel W.

AU - Gaillard, Aleth

AU - Kolb, Kellie E.

AU - Villani, Alexandra Chloé

AU - Johannessen, Cory M.

AU - Andreev, Aleksandr Y.

AU - Van Allen, Eliezer M.

AU - Bertagnolli, Monica

AU - Sorger, Peter K.

AU - Sullivan, Ryan J.

AU - Flaherty, Keith T.

AU - Frederick, Dennie T.

AU - Jané-Valbuena, Judit

AU - Yoon, Charles H.

AU - Rozenblatt-Rosen, Orit

AU - Shalek, Alex K.

AU - Regev, Aviv

AU - Garraway, Levi A.

PY - 2016/4/8

Y1 - 2016/4/8

N2 - 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 Tcell 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.

AB - 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 Tcell 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.

UR - http://www.scopus.com/inward/record.url?scp=84963614956&partnerID=8YFLogxK

U2 - https://doi.org/10.1126/science.aad0501

DO - https://doi.org/10.1126/science.aad0501

M3 - Article

C2 - 27124452

SN - 0036-8075

VL - 352

SP - 189

EP - 196

JO - Science

JF - Science

IS - 6282

ER -

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

Abstract

All Science Journal Classification (ASJC) codes

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