Spatial profiling of central nervous system cellular markers in murine breast cancer to brain metastases

BackgroundBrain metastasis occurs in approximately 16% of metastatic breast cancer patients, and incidence is increasing. Patients with breast cancer brain metastases frequently develop neurological problems including cognitive impairments and seizures. We previously demonstrated accumulation of activated microglia around the tumour site in a breast cancer brain metastasis model, which co-localised with spontaneously occurring local field potential events that resembled interictal epileptic discharges. However, the mechanisms underlying these spatially restricted effects on neuronal excitability are poorly understood. MethodsTo better understand the underlying cellular changes and potential mechanisms, we used digital spatial profiling of brain cell subtype-specific markers to chart the spatial organisation of neurons, oligodendrocytes, astrocytes, and microglia in relation to metastatic lesion site. We developed a novel chordline-based approach to analyse these spatial changes in biomarker distribution. ResultsSeveral protein markers associated with proliferation (Ki67), astrocytes (GFAP) and microglia (CD11b, IBA1, CD45, MSR1) were upregulated in the tumour compared to healthy contralateral brain parenchyma. In contrast, some neuroglial markers (MAP2, Neurofilament light, NeuN, S100B and TMEM119) were lower in the lesion compared to normal tissue. ConclusionsOverall, the protein marker changes in the lesion are indicative of neuronal cell loss and changes in the immune microenvironment of the metastatic lesion involving activated microglia, astrocytes and recruitment of peripheral immune cells. Such cellular changes may contribute to the changes in electrical activity resulting from brain metastases observed in mice and patients.