Interrogation of endothelial and mural cells in brain metastasis by multiomic analysis reveals key immune-regulatory mechanisms
Brain metastasis (BrM) represents the most common and aggressive brain malignancy, predominantly arising from non-small cell lung cancer, breast cancer, and melanoma. Recent studies have revealed the importance of the brain tumor microenvironment (TME), notably diverse immune cells, which play important roles in regulating cancer progression in both primary and metastatic brain malignancies. The blood-brain barrier (BBB) is another critical TME component formed by endothelial cells, mural cells, astrocytic end-feet, and closely-associated microglial cells. Metastasizing cancer cells can utilize different strategies to traverse the BBB and once they have successfully seeded and colonized the brain, they can exploit the vasculature for their own benefit, forming the blood-tumor barrier. To explore the mechanisms underlying tumor vascularization in brain metastasis we performed a comprehensive multiomic analysis of the key components of the tumor vasculature. We integrated single-cell and/or bulk RNA sequencing of sorted endothelial and mural cells isolated from human and mouse BrM and non-tumor samples; immunofluorescence imaging analysis of the spatial architecture of the TME; and functional studies using BrM mouse models to target vascular regulators of tumor immunity. Our results provide a comprehensive understanding of the biology underlying vascularization in metastatic brain tumors, specifically highlighting the importance of vascular cells as immune regulators and proposing novel therapeutic strategies for these aggressive tumors. Overall design: Expression profile of endothelial and mural cells in BrM versus non-tumor brain tissue.