Cellular Architecture of Human Brain Metastases
Summary
Brain metastasis (BrM) constitutes the most prevalent cerebral malignancy, typified by neurological debilitation and a woefully unfavorable prognosis. Regrettably, our comprehension of the biological underpinnings of human BrMs remains embryonic. The authors herein proffer a comprehensive examination of over 100,000 malignant and non-malignant cells procured from 15 human parenchymal BrMs, employing single-cell transcriptomics, mass cytometry, and supplemented with murine model and in silico methodologies. They scrutinize BrM microenvironmental constituents, delineate the blood-tumor nexus molecularly, and unveil stromal immunosuppressive states replete with infiltrating T cells and macrophages. Through fastidious single-cell exploration of metastatic neoplastic cells, they devise a schematic encompassing eight concomitant or anticorrelated functional cell programs. In tandem, these programs demarcate two distinct functional BrM archetypes - a proliferative and an inflammatory one - which ostensibly evolve via tumor-immune interplay. This invaluable compendium furnishes the groundwork for elucidating the molecular foundations of BrM in patients, incorporating neoplastic cell-intrinsic and host environmental aspects.
Fig.1 Graphical abstract. (Gonzalez, 2022)
Research Criteria
The scientific goal of this research is to provide an in-depth dissection of over 100,000 malignant and non-malignant cells from 15 human parenchymal BrMs using single-cell transcriptomics, mass cytometry, and murine model and in silico techniques. The study looks at BrM microenvironmental components, delineates the blood-tumor nexus at the molecular level, and reveals stromal immunosuppressive states with infiltrating T cells and macrophages. A schematic incorporating eight concurrent or anticorrelated functional cell programs is constructed after thorough single-cell investigation. Our programs identify two unique functional BrM archetypes, one proliferative and one inflammatory, that apparently arise through tumor-immune interactions. This fundamental work elucidates the molecular underpinnings of BrM, taking into account both neoplastic cell intrinsic and host environmental factors.
Fig.2 Experimental design. (Gonzalez, 2022)
Sample Type
Human brain tumor samples.
Result—Brain Metastases from Different Cancer Types Reveal Comparable Metastatic Niches
The research investigation meticulously examined pristine parenchymal brain metastasis (BrM) samples procured from fifteen patients afflicted with an array of malignancies, including melanoma, breast cancer, lung cancer, ovarian cancer, colorectal cancer (CRC), renal cell carcinoma, unknown primary carcinoma, and a rare case of adult rhabdomyosarcoma. These specimens, predominantly situated within the cerebral cortex, coalesced into shared and markedly distinct conglomerates, enabling researchers to annotate cell types utilizing cluster-specific markers. Intriguingly, stromal cells originating from diverse neoplasms formed shared and conspicuously segregated clusters, while metastatic tumor cells generated autonomous clusters, devoid of any intermingling between individual cases. This phenomenon underscored the considerable inter-patient transferability of the findings, shedding new light on the underlying cellular mechanisms of these malignancies.
Fig.3 Cellular census of human brain metastases using scRNA-seq analysis. (Gonzalez, 2022)
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Reference
- Gonzalez, H.; et al. Cellular architecture of human brain metastases. Cell. 2022, 185(4): 729-745.
