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Dissecting the treatment-naive ecosystem of human melanoma brain metastasis.

Updated June 5, 2023

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 macrophages 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.

Jana BiermannDepartment of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Program for Mathematical Genomics, Columbia University, New York, NY 10032, USA.jb4424@cumc.columbia.edu
Jana Biermann1
Johannes C Melms2
Amit Dipak Amin2
Yiping Wang1
Lindsay A Caprio2
Alcida Karz3
Somnath Tagore4
Irving Barrera5
Miguel A Ibarra-Arellano6
Massimo Andreatta7
Benjamin T Fullerton8
Kristjan H Gretarsson9
Varun Sahu9
Vaibhav S Mangipudy9
Trang T T Nguyen10
Ajay Nair8
Meri Rogava2
Patricia Ho2
Peter D Koch11
Matei Banu12
Nelson Humala12
Aayushi Mahajan12
Zachary H Walsh11
Shivem B Shah11
Daniel H Vaccaro11
Blake Caldwell11
Michael Mu11
Florian Wünnemann6
Margot Chazotte6
Simon Berhe8
Adrienne M Luoma13
Joseph Driver14
Matthew Ingham8
Shaheer A Khan8
Suthee Rapisuwon15
Craig L Slingluff16
Thomas Eigentler17
Martin Röcken18
Richard Carvajal8
Michael B Atkins19
Michael A Davies20
Albert Agustinus21
Samuel F Bakhoum22
Elham Azizi23
Markus Siegelin10
Chao Lu9
Santiago J Carmona7
Hanina Hibshoosh10
Antoni Ribas24
Peter Canoll10
Jeffrey N Bruce12
Wenya Linda Bi25
Praveen Agrawal26
Denis Schapiro27
Eva Hernando3
Evan Z Macosko28
Fei Chen29
Gary K Schwartz8
Benjamin Izar30
1Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Program for Mathematical Genomics, Columbia University, New York, NY 10032, USA.
2Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA.
3Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA.
4Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
5Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
6Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, 69120 Heidelberg, Germany.
7Department of Oncology UNIL CHUV, Lausanne Branch, Ludwig Institute for Cancer Research Lausanne, CHUV and University of Lausanne, Lausanne, 1066 Épalinges, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland.
8Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
9Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
10Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
11Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
12Department of Neurological Surgery, New York Presbyterian/Columbia University Irving Medical Center, New York, NY 10032, USA.
13Department of Cancer Immunology and Virology, Dana-Farber Cancer Center, Boston, MA 02215, USA.
14Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
15Division of Hematology/Oncology, Medstar Washington Cancer Institute, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
16Department of Surgery, University of Virginia, Charlottesville, VA, USA.
17Department of Dermatology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany; Charité-Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Dermatology, Venereology and Allergology, 10117, Berlin, Germany.
18Department of Dermatology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
19Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
20Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA.
21Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Department of Pharmacology, Weill Cornell Graduate School, New York, NY 10065, USA.
22Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
23Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA; Irving Institute for Cancer Dynamics, Columbia University, New York, NY 10027, USA.
24Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA), Los Angeles, CA 90024, USA.
25Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
26Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA.
27Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, 69120 Heidelberg, Germany; Institute of Pathology, Heidelberg University Hospital, 69120 Heidelberg, Germany.
28Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA.
29Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA.
30 Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
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To reference this project, please use the following link:

https://explore.data.humancellatlas.org/projects/0efecd20-2b52-4e4f-96c5-9b4b94158713
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GEO Series Accessions:

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Analysis Portals

None

Project Label

melanomaBrainMetastasisAtlas

Species

Homo sapiens

Sample Type

2 sample types

Anatomical Entity

5 anatomical entities

Organ Part

Unspecified

Selected Cell Types

Unspecified

Model Organ

brain

Disease Status (Specimen)

metastatic melanoma

Disease Status (Donor)

metastatic melanoma

Development Stage

human adult stage

Library Construction Method

6 library construction methods

Nucleic Acid Source

4 nucleic acid sources

Paired End

false, true

Analysis Protocol

analysis_protocol_1, analysis_protocol_10, analysis_protocol_2, analysis_protocol_3, analysis_protocol_4, analysis_protocol_5, analysis_protocol_6, analysis_protocol_7, analysis_protocol_8, analysis_protocol_9

File Format

4 file formats

Cell Count Estimate

114.5k

Donor Count

36
csv.gz8 file(s)mtx.gz1 file(s)tar4 file(s)xlsx1 file(s)