Cellular Architecture of Human Brain Metastases

2021 
Brain metastasis (BrM) is the most common form of brain cancer, characterized by neurologic disability and 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 as a resource, 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 reveal stromal immunosuppressive states, enriched with infiltrated T cells and macrophages. Specific single-cell interrogation of metastatic tumor cells provides a novel 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.
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