Tumour-derived secreted phosphoprotein 1/SPP1 via activation of microglia contributes to the formation of the breast cancer brain metastatic niche

Brain metastases (BrMets) occur in 20%-40% of patients with breast cancer and contribute significantly to morbidity and/or mortality. BrMets are more common in certain breast cancer subtypes, such as human epidermal growth factor receptor 2–positive breast cancer, which has a higher incidence of BrMets. The molecular mechanisms that drive and permit the progression of metastasis in the brain are poorly understood. Identifying components of the metastatic niches and propensities of primary tumors towards the brain microenvironment are essential to improve our understanding of BrMet development, patient management and outcomes. SPP1, a secreted phosphoglycoprotein 1, is a potent activator of microglia (brain resident myeloid cells) in malignant gliomas. SPP1 is elevated in breast cancer and breast cancer brain metastasis. Exploration of public bulk and scRNAseq datasets shows high SPP1 overexpression in breast malignant cells, as well as in the immune cells in BrMets. We found that breast cancer cells with high expression of SPP1 strongly activate microglia in co-cultures, which in turn increases cancer cell invasion. Blocking SPP1-mediated cancer-microglia communication with the 7aaRGD interfering peptide or shRNA mediated knockdown of SPP1 in cancer cells, abolished microglia-dependent cancer cell invasion. Notably, we found that an antibiotic minocycline efficiently reduces the expression of SPP1 in several breast cancer cell lines, and decreases both the basal and microglia-induced invasion of breast cancer cells. The results highlight the important role of breast cancer-derived SPP1 in shaping the permissive microenvironment of BrMet, and indicate a potential of the 7aaRGD peptide or minocycline to be new therapeutics in breast cancer brain metastasis treatment.