Dissecting the treatment-naive ecosystem of human melanoma brain metastasis

被引：113

作者：

Biermann, Jana ^{[1
,2
,3
]}

Melms, Johannes C. ^{[1
,2
,4
]}

Amin, Amit Dipak ^{[1
,2
,4
]}

Wang, Yiping ^{[1
,2
,3
]}

Caprio, Lindsay A. ^{[1
,2
,4
]}

Karz, Alcida ^{[5
]}

Tagore, Somnath ^{[6
]}

Barrera, Irving ^{[7
]}

Ibarra-Arellano, Miguel A. ^{[8
,9
]}

Andreatta, Massimo ^{[10
,11
,12
]}

Fullerton, Benjamin T. ^{[1
,2
]}

Gretarsson, Kristjan H. ^{[13
]}

Sahu, Varun ^{[13
]}

Mangipudy, Vaibhav S. ^{[13
]}

Nguyen, Trang T. T. ^{[14
]}

Nair, Ajay ^{[1
,2
]}

Rogava, Meri ^{[1
,2
,4
]}

Ho, Patricia ^{[1
,2
,4
]}

Koch, Peter D. ^{[15
]}

Banu, Matei ^{[16
]}

Humala, Nelson ^{[16
]}

Mahajan, Aayushi ^{[16
]}

Walsh, Zachary H. ^{[15
]}

Shah, Shivem B. ^{[15
]}

Vaccaro, Daniel H. ^{[15
]}

Caldwell, Blake ^{[15
]}

Mu, Michael ^{[15
]}

Wuennemann, Florian ^{[8
,9
]}

Chazotte, Margot ^{[8
,9
]}

Berhe, Simon ^{[1
,2
]}

Luoma, Adrienne M. ^{[17
]}

Driver, Joseph ^{[18
]}

Ingham, Matthew ^{[1
,2
]}

Khan, Shaheer A. ^{[1
,2
]}

Rapisuwon, Suthee ^{[19
]}

Slingluff, Craig L., Jr. ^{[20
]}

Eigentler, Thomas ^{[21
,22
,23
,24
,25
]}

Roecken, Martin ^{[21
]}

Carvajal, Richard ^{[1
,2
]}

Atkins, Michael B. ^{[26
]}

Davies, Michael A. ^{[27
]}

Agustinus, Albert ^{[28
,29
]}

Bakhoum, Samuel F. ^{[27
,28
]}

Azizi, Elham ^{[30
,31
]}

Siegelin, Markus ^{[14
]}

Lu, Chao ^{[13
]}

Carmona, Santiago J. ^{[10
,11
,12
]}

Hibshoosh, Hanina ^{[14
]}

Ribas, Antoni ^{[32
]}

Canoll, Peter ^{[14
]}

机构：

[1] Columbia Univ, Dept Med, Div Hematol Oncol, Irving Med Ctr, New York, NY 10032 USA

[2] Columbia Univ, Herbert Irving Comprehens Canc Ctr, Irving Med Ctr, New York, NY 10032 USA

[3] Columbia Univ, Program Math Genom, New York, NY 10032 USA

[4] Columbia Univ, Columbia Ctr Translat Immunol, Irving Med Ctr, New York, NY 10032 USA

[5] NYU Grossman Sch Med, Dept Pathol, New York, NY 10016 USA

[6] Columbia Univ, Dept Syst Biol, Irving Med Ctr, New York, NY 10032 USA

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

[8] Heidelberg Univ, Fac Med, D-69120 Heidelberg, Germany

[9] Heidelberg Univ Hosp, Inst Computat Biomed, Bioquant, D-69120 Heidelberg, Germany

[10] CHUV, Dept Oncol UNIL CHUV, Lausanne Branch, Ludwig Inst Canc Res Lausanne, CH-1066 Epalinges, Switzerland

[11] Univ Lausanne, CH-1066 Epalinges, Switzerland

[12] Swiss Inst Bioinformat, CH-1015 Lausanne, Switzerland

[13] Columbia Univ, Dept Genet & Dev, Med Ctr, New York, NY 10032 USA

[14] Columbia Univ, Dept Pathol & Cell Biol, Med Ctr, New York, NY 10032 USA

[15] Columbia Univ, Vagelos Coll Phys & Surg, New York, NY 10032 USA

[16] Columbia Univ, Dept Neurol Surg, New York Presbyterian, Irving Med Ctr, New York, NY 10032 USA

[17] Dana Farber Canc Ctr, Dept Canc Immunol & Virol, Boston, MA 02215 USA

[18] Harvard Med Sch, Dept Neurosurg, Brigham & Womens Hosp, Boston, MA 02115 USA

[19] Georgetown Univ, Med Ctr, Lombardi Comprehens Canc Ctr, Div Hematol Oncol,Medstar Washington Canc Inst, Washington, DC 20007 USA

[20] Univ Virginia, Dept Surg, Charlottesville, VA USA

[21] Eberhard Karls Univ Tubingen, Dept Dermatol, D-72076 Tubingen, Germany

[22] Charite Univ Med Berlin, D-10117 Berlin, Germany

[23] Free Univ Berlin, D-10117 Berlin, Germany

[24] Humboldt Univ, D-10117 Berlin, Germany

[25] Dept Dermatol Venereol & Allergol, D-10117 Berlin, Germany

[26] Georgetown Univ, Georgetown Lombardi Comprehens Canc Ctr, Med Ctr, Washington, DC 20007 USA

[27] MD Anderson Canc Ctr, Dept Melanoma Med Oncol, Houston, TX 77030 USA

[28] Mem Sloan Kettering Canc Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA

[29] Weill Cornell Grad Sch, Dept Pharmacol, New York, NY 10065 USA

[30] Columbia Univ, Dept Biomed Engn, New York, NY 10027 USA

[31] Columbia Univ, Irving Inst Canc Dynam, New York, NY 10027 USA

[32] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Dept Med, Los Angeles, CA 90024 USA

[33] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02215 USA

[34] Albert Einstein Coll Med, Dept Mol Pharmacol, New York, NY 10461 USA

[35] Heidelberg Univ Hosp, Inst Pathol, D-69120 Heidelberg, Germany

[36] Massachusetts Gen Hosp, Dept Psychiat, Boston, MA 02114 USA

[37] Harvard Univ, Dept Stem Cell & Regenerat Biol, Cambridge, MA 02138 USA

来源：

CELL | 2022年 / 185卷 / 14期

关键词：

RNA-SEQ DATA; SINGLE-CELL; GENOMIC CHARACTERIZATION; CHROMOSOMAL INSTABILITY; IN-VIVO; INFERENCE; CANCER; INTEGRATION; RESISTANCE; CHROMATIN;

D O I：

10.1016/j.cell.2022.06.007

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Melanoma brain metastasis (MBM) frequently occurs in patients with advanced melanoma; yet, our understanding of the underlying salient biology is rudimentary. Here, we performed single-cell/nucleus RNA-seq in 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs) and matched spatial single-cell transcriptomics and T cell receptor (TCR)-seq. Cancer cells from MBM were more chromosomally unstable, adopted a neuronal-like cell state, and enriched for spatially variably expressed metabolic pathways. Key observations were validated in independent patient cohorts, patient-derived MBM/ECM xenograft models, RNA/ATAC-seq, proteomics, and multiplexed imaging. Integrated spatial analyses revealed distinct geography of putative cancer immune evasion and evidence for more abundant intra-tumoral B to plasma cell differentiation in lymphoid aggregates in MBM. MBM harbored larger fractions of monocyte-derived macro-phages and dysfunctional TOX(+)CD8(+) T cells with distinct expression of immune checkpoints. This work provides comprehensive insights into MBM biology and serves as a foundational resource for further discovery and therapeutic exploration.

引用

页码：2591 / +

页数：49

共 129 条

[1] Integration of ATAC-seq and RNA-seq identifies human alpha cell and beta cell signature genes [J].

Ackermann, Amanda M. ;

Wang, Zhiping ;

Schug, Jonathan ;

Naji, Ali ;

Kaestner, Klaus H. .

MOLECULAR METABOLISM, 2016, 5 (03) :233-244

[2] Disabled homolog 2 controls macrophage phenotypic polarization and adipose tissue inflammation [J].

Adamson, Samantha E. ;

Griffiths, Rachael ;

Moravec, Radim ;

Senthivinayagam, Subramanian ;

Montgomery, Garren ;

Chen, Wenshu ;

Han, Jenny ;

Sharma, Poonam R. ;

Mullins, Garrett R. ;

Gorski, Stacey A. ;

Cooper, Jonathan A. ;

Kadl, Alexandra ;

Enfield, Kyle ;

Braciale, Thomas J. ;

Harris, Thurl E. ;

Leitinger, Norbert .

JOURNAL OF CLINICAL INVESTIGATION, 2016, 126 (04) :1311-1322

[3]

Aibar S, 2017, NAT METHODS, V14, P1083, DOI [10.1038/NMETH.4463, 10.1038/nmeth.4463]

[4] Genomic Classification of Cutaneous Melanoma [J].

Akbani, Rehan ;

Akdemir, Kadir C. ;

Aksoy, B. Arman ;

Albert, Monique ;

Ally, Adrian ;

Amin, Samirkumar B. ;

Arachchi, Harindra ;

Arora, Arshi ;

Auman, J. Todd ;

Ayala, Brenda ;

Baboud, Julien ;

Balasundaram, Miruna ;

Balu, Saianand ;

Barnabas, Nandita ;

Bartlett, John ;

Bartlett, Pam ;

Bastian, Boris C. ;

Baylin, Stephen B. ;

Behera, Madhusmita ;

Belyaev, Dmitry ;

Benz, Christopher ;

Bernard, Brady ;

Beroukhim, Rameen ;

Bir, Natalie ;

Black, Aaron D. ;

Bodenheimer, Tom ;

Boice, Lori ;

Boland, Genevieve M. ;

Bono, Riccardo ;

Bootwalla, Moiz S. ;

Bosenberg, Marcus ;

Bowen, Jay ;

Bowlby, Reanne ;

Bristow, Christopher A. ;

Brockway-Lunardi, Laura ;

Brooks, Denise ;

Brzezinski, Jakub ;

Bshara, Wiam ;

Buda, Elizabeth ;

Burns, William R. ;

Butterfield, Yaron S. N. ;

Button, Michael ;

Calderone, Tiffany ;

Cappellini, Giancarlo Antonini ;

Carter, Candace ;

Carter, Scott L. ;

Cherney, Lynn ;

Cherniack, Andrew D. ;

Chevalier, Aaron ;

Chin, Lynda .

CELL, 2015, 161 (07) :1681-1696

[5]

Alberti G., 2021, GmAMisc: "Gianmarco Alberti" Miscellaneous v.1.2.0. R Package (v.1.2.0)

[6] Functional characterization of somatic mutations in cancer using network-based inference of protein activity [J].

Alvarez, Mariano J. ;

Shen, Yao ;

Giorgi, Federico M. ;

Lachmann, Alexander ;

Ding, B. Belinda ;

Ye, B. Hilda ;

Califano, Andrea .

NATURE GENETICS, 2016, 48 (08) :838-+

[7]

AMEMIYA HM, 2019, SCI REP-UK, V91, P1

[8] Interpretation of T cell states from single-cell transcriptomics data using reference atlases [J].

Andreatta, Massimo ;

Corria-Osorio, Jesus ;

Muller, Soren ;

Cubas, Rafael ;

Coukos, George ;

Carmona, Santiago J. .

NATURE COMMUNICATIONS, 2021, 12 (01)

[9] STACAS: Sub-Type Anchor Correction for Alignment in Seurat to integrate single-cell RNA-seq data [J].

Andreatta, Massimo ;

Carmona, Santiago J. .

BIOINFORMATICS, 2021, 37 (06) :882-884

[10] destiny: diffusion maps for large-scale single cell data in R [J].

Angerer, Philipp ;

Haghverdi, Laleh ;

Buettner, Maren ;

Theis, Fabian J. ;

Marr, Carsten ;

Buettner, Florian .

BIOINFORMATICS, 2016, 32 (08) :1241-1243

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