Cellular and molecular signatures of the vascular microenvironment define the pre-metastatic brain and meninges [MERFISH]

Here, we characterise the pre-metastatic molecular changes that occur in brain and meningeal resident cells in mouse models of breast cancer using single-cell and spatial transcriptomics. Increased inflammatory alterations preceding metastasis were identified in bridging veins spanning the leptomeninges, forming adhesion hotspots by upregulating Icam1 and Vcam1.

Furthermore, bridging veins and encapsulating leptomeningeal fibroblasts upregulate cell trafficking ligands, including chemokines. Brain metastasising tumour cells correspondingly upregulate adhesion counter-receptor LFA-1 and chemokine receptors, demonstrating an enhanced capacity to traffic towards altered brain vessels and stroma. Moreover, PD-L1+ immunosuppressive neutrophils infiltrate the dura and brain, coupled with upregulation of checkpoint molecule PD-1 in CD8+ T cells.