Dissecting the treatment-naive ecosystem of human melanoma brain metastasis

Jana Biermann; Johannes C Melms; Amit Dipak Amin; Yiping Wang; Lindsay A Caprio; Alcida Karz; Somnath Tagore; Irving Barrera; Miguel A Ibarra-Arellano; Massimo Andreatta; Benjamin T Fullerton; Kristjan H Gretarsson; Varun Sahu; Vaibhav S Mangipudy; Trang T T Nguyen; Ajay Nair; Meri Rogava; Patricia Ho; Peter D Koch; Matei Banu; Nelson Humala; Aayushi Mahajan; Zachary H Walsh; Shivem B Shah; Daniel H Vaccaro; Blake Caldwell; Michael Mu; Florian Wünnemann; Margot Chazotte; Simon Berhe; Adrienne M Luoma; Joseph Driver; Matthew Ingham; Shaheer A Khan; Suthee Rapisuwon; Craig L Slingluff Jr; Thomas Eigentler; Martin Röcken; Richard Carvajal; Michael B Atkins; Michael A Davies; Albert Agustinus; Samuel F Bakhoum; Elham Azizi; Markus Siegelin; Chao Lu; Santiago J Carmona; Hanina Hibshoosh; Antoni Ribas; Peter Canoll; Jeffrey N Bruce; Wenya Linda Bi; Praveen Agrawal; Denis Schapiro; Eva Hernando; Evan Z Macosko; Fei Chen; Gary K Schwartz; Benjamin Izar

doi:10.1016/j.cell.2022.06.007

Dissecting the treatment-naive ecosystem of human melanoma brain metastasis

Cell. 2022 Jul 7;185(14):2591-2608.e30. doi: 10.1016/j.cell.2022.06.007.

Authors

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 Slingluff Jr¹⁶, 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

Affiliations

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 Pathology, NYU Grossman School of Medicine, New York, NY 10016, USA.
⁴ Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁵ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA.
⁶ Heidelberg University, Faculty of Medicine, and Heidelberg University Hospital, Institute for Computational Biomedicine, Bioquant, 69120 Heidelberg, Germany.
⁷ Department 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.
⁸ Department of Medicine, Division of Hematology/Oncology, and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY 10032, USA.
⁹ Department of Genetics and Development, Columbia University Medical Center, New York, NY 10032, USA.
¹⁰ Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY 10032, USA.
¹¹ Columbia University Vagelos College of Physicians and Surgeons, New York, NY 10032, USA.
¹² Department of Neurological Surgery, New York Presbyterian/Columbia University Irving Medical Center, New York, NY 10032, USA.
¹³ Department of Cancer Immunology and Virology, Dana-Farber Cancer Center, Boston, MA 02215, USA.
¹⁴ Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹⁵ Division of Hematology/Oncology, Medstar Washington Cancer Institute, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
¹⁶ Department of Surgery, University of Virginia, Charlottesville, VA, USA.
¹⁷ Department 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.
¹⁸ Department of Dermatology, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
¹⁹ Georgetown-Lombardi Comprehensive Cancer Center, Georgetown University Medical Center, Washington, DC 20007, USA.
²⁰ Department of Melanoma Medical Oncology, MD Anderson Cancer Center, Houston, TX 77030, USA.
²¹ 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.
²² 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.
²³ Department of Biomedical Engineering, Columbia University, New York, NY 10027, USA; Irving Institute for Cancer Dynamics, Columbia University, New York, NY 10027, USA.
²⁴ Department of Medicine, Jonsson Comprehensive Cancer Center, University of California, Los Angeles (UCLA), Los Angeles, CA 90024, USA.
²⁵ 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.
²⁶ Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York, NY 10461, USA.
²⁷ 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.
²⁸ Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA; Department of Psychiatry, Massachusetts General Hospital, Boston, MA 02114, USA.
²⁹ Broad 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; 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.

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.

Keywords: brain metastasis; chromosomal instability; melanoma; neuronal-like cell state; single-cell genomics; spatial transcriptomics; tumor-microenvironment.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Brain Neoplasms* / drug therapy
Brain Neoplasms* / secondary
CD8-Positive T-Lymphocytes / pathology
Ecosystem
Humans
Melanoma*
RNA-Seq

Abstract

Publication types

MeSH terms

Grants and funding