Cellular architecture of human brain metastases

Hugo Gonzalez; Wenbin Mei; Isabella Robles; Catharina Hagerling; Breanna M Allen; Trine Line Hauge Okholm; Ankitha Nanjaraj; Tamara Verbeek; Sandhya Kalavacherla; Merel van Gogh; Stephen Georgiou; Mariza Daras; Joanna J Phillips; Matthew H Spitzer; Jeroen P Roose; Zena Werb

doi:10.1016/j.cell.2021.12.043

Cellular architecture of human brain metastases

Cell. 2022 Feb 17;185(4):729-745.e20. doi: 10.1016/j.cell.2021.12.043. Epub 2022 Jan 20.

Authors

Hugo Gonzalez¹, Wenbin Mei², Isabella Robles², Catharina Hagerling³, Breanna M Allen⁴, Trine Line Hauge Okholm⁵, Ankitha Nanjaraj², Tamara Verbeek², Sandhya Kalavacherla², Merel van Gogh², Stephen Georgiou², Mariza Daras⁶, Joanna J Phillips⁷, Matthew H Spitzer⁸, Jeroen P Roose⁹, Zena Werb¹⁰

Affiliations

¹ Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-0452, USA. Electronic address: [email protected].
² Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-0452, USA.
³ Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-0452, USA; Department of Laboratory Medicine, Division of Clinical Genetics, Lund University, SE 221 85 Lund, Sweden.
⁴ Graduate Program in Biomedical Sciences, University of California, San Francisco, San Francisco, CA, USA; Departments of Otolaryngology-Head and Neck Surgery and Microbiology & Immunology, Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, CA, USA.
⁵ Departments of Otolaryngology-Head and Neck Surgery and Microbiology & Immunology, Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, CA, USA.
⁶ Department of Neurological Surgery, University of California, San Francisco, 1450 3rd Street, San Francisco, CA 94158, USA.
⁷ Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA; Department of Neurological Surgery, University of California, San Francisco, 1450 3rd Street, San Francisco, CA 94158, USA.
⁸ Graduate Program in Biomedical Sciences, University of California, San Francisco, San Francisco, CA, USA; Departments of Otolaryngology-Head and Neck Surgery and Microbiology & Immunology, Parker Institute for Cancer Immunotherapy, Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, CA, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.
⁹ Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-0452, USA. Electronic address: [email protected].
¹⁰ Department of Anatomy, University of California, San Francisco, San Francisco, CA 94143-0452, USA; Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA 94143, USA.

Abstract

Brain metastasis (BrM) is the most common form of brain cancer, characterized by neurologic disability and an abysmal prognosis. Unfortunately, our understanding of the biology underlying human BrMs remains rudimentary. Here, we present an integrative analysis of >100,000 malignant and non-malignant cells from 15 human parenchymal BrMs, generated by single-cell transcriptomics, mass cytometry, and complemented with mouse model- and in silico approaches. We interrogated the composition of BrM niches, molecularly defined the blood-tumor interface, and revealed stromal immunosuppressive states enriched with infiltrated T cells and macrophages. Specific single-cell interrogation of metastatic tumor cells provides a framework of 8 functional cell programs that coexist or anticorrelate. Collectively, these programs delineate two functional BrM archetypes, one proliferative and the other inflammatory, that are evidently shaped through tumor-immune interactions. Our resource provides a foundation to understand the molecular basis of BrM in patients with tumor cell-intrinsic and host environmental traits.

Keywords: CyTOF; blood tumor barrier; human metastasis; metastasis-associated macrophages; metastasis-infiltrated T cells; metastatic niche; metastatic program; metastatic tumor cells; metastatic tumors; single cell.

Publication types

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

MeSH terms

Adult
Aged
Animals
Biomarkers, Tumor / metabolism
Brain Neoplasms / blood
Brain Neoplasms / immunology
Brain Neoplasms / pathology*
Brain Neoplasms / secondary*
Cell Cycle
Cell Line, Tumor
Cell Proliferation
Female
Genetic Variation
Humans
Immune Evasion
Lymphocyte Activation / immunology
Lymphocytes, Tumor-Infiltrating / immunology
Mice
Mice, Inbred BALB C
Mice, Nude
Middle Aged
Models, Biological
Myeloid Cells / pathology
Principal Component Analysis
RNA-Seq
Single-Cell Analysis
T-Lymphocytes / immunology

Substances

Biomarkers, Tumor

Abstract

Publication types

MeSH terms

Substances

Grants and funding