Loss of XIST in breast cancer activates MSN-c-Met and reprograms microglia via exosomal microRNA to promote brain metastasis

Up to 30% of patients with metastatic breast cancer eventually develop brain metastasis, yet the pathological mechanism behind this development remains poorly understood. Here we profiled long non-coding RNAs in brain metastatic tumors from breast cancer patients and found that the X-inactive specific transcript (XIST) was significantly downregulated in these tissues. XIST expression levels inversely correlated with brain metastasis, but not with bone metastasis in patients. Silencing of XIST preferentially promoted brain metastatic growth of XIST high cells in our xenograft models. Moreover, knockout of XIST in mice mammary glands accelerated primary tumor growth as well as metastases in the brain. Decreased expression of XIST stimulated epithelial-mesenchymal-transition (EMT) and activated c-Met via MSN-mediated protein stabilization, which resulted in the promotion of stemness in the tumor cells. Loss of XIST also augmented secretion of exosomal microRNA-503, which triggered M1-M2 polarization of microglia. This M1-M2 conversion upregulated immune suppressive cytokines in microglia which suppressed T-cell proliferation. Furthermore, we screened an FDA-approved drug library and identified fludarabine as a synthetic lethal drug for XIST low breast tumor cells and found that fludarabine blocked brain metastasis in our animal model. Our results indicate that XIST plays a critical role in brain metastasis in breast cancer by affecting both tumor cells and the tumor microenvironment, and that the XIST-mediated pathway may serve as an effective target for treating brain metastasis.