Melanoma brain metastases (MBM) are common in patients with advanced melanoma, but the underlying biology is poorly understood. To address this gap, Biermann and Melms et al. compared multi-modal single cell transcriptomics of 22 treatment-naive MBMs and 10 extracranial melanoma metastases (ECMs; MBM and ECM were from different patients), coupled with functional validation in human and mouse models. MBM cells adopted a neuronal-like phenotype associated with increased chromosomal instability, and contained increased numbers of pro-tumorigenic macrophages and dysfunctional TOX+CD8+ T cells compared with ECMs.
Contributed by Katherine Turner
ABSTRACT: 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.
Author Info: (1) Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA; Pro
Author Info: (1) Department 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. (2) Department 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. (3) Department 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. (4) Department 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. (5) Department 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. (6) Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA. (7) Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA. (8) Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA. (9) Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, 69120 Heidelberg, Germany. (10) Department of Oncology UNIL CHUV, Lausanne Branch, Ludwig Institute for Cancer Research Lausanne, CHUV and University of Lausanne, Lausanne, 1066 palinges, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland. (11) Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. (12) Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA. (13) Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA. (14) Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA. (15) Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. (16) Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. (17) Department 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. (18) Department 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. (19) Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. (20) Department of Neurological Surgery, New York Presbyterian/Columbia University Irving Medical Center, New York, NY 10032, USA. (21) Department of Neurological Surgery, New York Presbyterian/Columbia University Irving Medical Center, New York, NY 10032, USA. (22) Department of Neurological Surgery, New York Presbyterian/Columbia University Irving Medical Center, New York, NY 10032, USA. (23) Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. (24) Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. (25) Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. (26) Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. (27) Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA. (28) Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, 69120 Heidelberg, Germany. (29) Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, 69120 Heidelberg, Germany. (30) Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. (31) Department of Cancer Immunology and Virology, Dana-Farber Cancer Center, Boston, MA 02215, USA. (32) Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. (33) Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. (34) Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. (35) Division of Hematology/Oncology, Medstar Washington Cancer Institute, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA. (36) Department of Surgery, University of Virginia, Charlottesville, VA, USA. (37) Department of Dermatology, Eberhard Karls University Tbingen, 72076 Tbingen, Germany; Charit-Universittsmedizin Berlin, Freie Universitt Berlin and Humboldt-Universitt zu Berlin, Department of Dermatology, Venereology and Allergology, 10117, Berlin, Germany. (38) Department of Dermatology, Eberhard Karls University Tbingen, 72076 Tbingen, Germany. (39) Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. (40) Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA. (41) Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA. (42) Human 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. (43) Department 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. (44) Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA; Irving Institute for Cancer Dynamics, Columbia University, New York, NY 10027, USA. (45) Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. (46) Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA. (47) Department of Oncology UNIL CHUV, Lausanne Branch, Ludwig Institute for Cancer Research Lausanne, CHUV and University of Lausanne, Lausanne, 1066 palinges, Switzerland; Swiss Institute of Bioinformatics, 1015 Lausanne, Switzerland. (48) Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. (49) Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA), Los Angeles, CA 90024, USA. (50) Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA. (51) Department of Neurological Surgery, New York Presbyterian/Columbia University Irving Medical Center, New York, NY 10032, USA. (52) Department 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. (53) Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA. (54) Heidelberg 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. (55) Department of Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA. (56) Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA. (57) Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA 02138, USA. (58) Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA. (59) Department 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; Columbia Center for Translational Immunology, Columbia University Irving Medical Center, New York, NY 10032, USA. Electronic address: bi2175@cumc.columbia.edu.
