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

被引：3180

作者：

Tirosh, Itay ^{[1
]}

Izar, Benjamin ^{[1
,2
,3
]}

Prakadan, Sanjay M. ^{[1
,4
,5
,6
,7
]}

Wadsworth, Marc H., II ^{[1
,4
,5
,6
,7
]}

Treacy, Daniel ^{[1
]}

Trombetta, John J. ^{[1
]}

Rotem, Asaf ^{[1
,2
,3
]}

Rodman, Christopher ^{[1
]}

Lian, Christine ^{[8
]}

Murphy, George ^{[8
]}

Fallahi-Sichani, Mohammad ^{[9
]}

Dutton-Regester, Ken ^{[1
,2
,10
]}

Lin, Jia-Ren ^{[11
]}

Cohen, Ofir ^{[1
]}

Shah, Parin ^{[2
]}

Lu, Diana ^{[1
]}

Genshaft, Alex S. ^{[1
,4
,5
,6
,7
]}

Hughes, Travis K. ^{[1
,4
,6
,7
,12
]}

Ziegler, Carly G. K. ^{[1
,4
,6
,7
,12
]}

Kazer, Samuel W. ^{[1
,4
,5
,6
,7
]}

Gaillard, Aleth ^{[1
,4
,5
,6
,7
]}

Kolb, Kellie E. ^{[1
,4
,5
,6
,7
]}

Villani, Alexandra-Chloe ^{[1
]}

Johannessen, Cory M. ^{[1
]}

Andreev, Aleksandr Y. ^{[1
]}

Van Allen, Eliezer M. ^{[1
,2
,3
]}

Bertagnolli, Monica ^{[13
,14
]}

Sorger, Peter K. ^{[9
,11
,15
]}

Sullivan, Ryan J. ^{[16
]}

Flaherty, Keith T. ^{[16
]}

Frederick, Dennie T. ^{[16
]}

Jane-Valbuena, Judit ^{[1
]}

Yoon, Charles H. ^{[13
,14
]}

Rozenblatt-Rosen, Orit ^{[1
]}

Shalek, Alex K. ^{[1
,4
,5
,6
,7
,12
,17
]}

Regev, Aviv ^{[1
,18
,19
,20
]}

Garraway, Levi A. ^{[1
,2
,3
,15
]}

机构：

[1] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[2] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[3] Dana Farber Canc Inst, Ctr Canc Precis Med, Boston, MA 02215 USA

[4] MIT, Inst Med Engn & Sci, Cambridge, MA 02139 USA

[5] MIT, Dept Chem, Cambridge, MA 02142 USA

[6] MIT, Massachusetts Gen Hosp, Ragon Inst, Cambridge, MA 02139 USA

[7] Harvard Univ, Cambridge, MA 02139 USA

[8] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[9] Harvard Univ, Sch Med, Dept Syst Biol, Program Therapeut Sci, Boston, MA 02115 USA

[10] QIMR Berghofer Med Res Inst, Dept Genet & Computat Biol, Brisbane, Qld, Australia

[11] Harvard Univ, Sch Med, HMS LINCS Ctr & Lab Syst Pharmacol, Boston, MA 02115 USA

[12] Harvard Univ, Sch Med, Div Hlth Sci & Technol, Boston, MA 02115 USA

[13] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Surg Oncol, Boston, MA 02215 USA

[14] Harvard Univ, Sch Med, Brigham & Womens Hosp, Dept Surg Oncol, Boston, MA 02215 USA

[15] Harvard Univ, Ludwig Ctr, Boston, MA 02215 USA

[16] Massachusetts Gen Hosp, Ctr Canc, Div Med Oncol, Boston, MA 02114 USA

[17] Massachusetts Gen Hosp, Dept Immunol, Boston, MA 02114 USA

[18] MIT, Dept Biol, Boston, MA 02142 USA

[19] MIT, Koch Inst, Boston, MA 02142 USA

[20] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

来源：

SCIENCE | 2016年 / 352卷 / 6282期

关键词：

CTLA-4; BLOCKADE; AXL KINASE; T-CELLS; SAFETY; RESISTANCE; NIVOLUMAB; CANCER; EXHAUSTION; EXPRESSION; HETEROGENEITY;

D O I：

10.1126/science.aad0501

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页码：189 / 196

页数：8

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