Loss of XIST in Breast Cancer Activates MSN-c-Met and Reprograms Microglia via Exosomal miRNA to Promote Brain Metastasis

Abstract

Up to 30% of patients with metastatic breast cancer eventually develop brain metastasis, yet the pathologic mechanism behind this development remains poorly understood. Here, we profiled long noncoding RNAs in brain metastatic tumors from patients with breast cancer 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 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 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 miRNA-503, which triggered M1-M2 polarization of microglia. This M1-M2 conversion upregulated immune suppressive cytokines in microglia that suppressed T-cell proliferation. Furthermore, we screened an FDA-approved drug library and identified fludarabine as a synthetic lethal drug for XIST 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. These findings describe mechanisms of how loss of the lncRNA XIST promotes brain metastasis in breast cancer and identify fludarabine as a potential therapeutic agent that specifically eliminates XIST tumor cells in the brain. .

LncRNA XIST promotes the progression of laryngeal squamous cell carcinoma via sponging miR-125b-5p to modulate TRIB2

“…Recently, miR-92b has been certified as a target inhibitor of XIST in hepatocellular carcinoma (HCC) [22]. Analogously, exosomal miRNA-503 was accumulated by loss of XIST resulting in tumor metastasis was repressed, which provided an attractive doctoring for breast cancer in the report of Xing et al [11]. These researches manifested that miRNAs had intimate association with lncRNA XIST.…”

Long Non-coding RNAs: Emerging Roles in the Immunosuppressive Tumor Microenvironment

“…FX is involved in the recruitment and M2-polarization of macrophages in glioblastoma (56). LncRNA X-inactive-specific transcript (XIST) functions as a tumor suppressor in brain-metastatic breast cancer (44). XIST was significantly downregulated in brain-metastatic tumors of patients with breast cancer.…”

“…The knockout of XIST in mammary glands of mice stimulated the growth of the primary tumor and brain metastases. Loss of XIST also enhanced the secretion of exosomal miRNA-503, which triggered the M2-polarization of microglia, and upregulated the immunosuppressive cytokines in microglia and subsequently suppressed T-cell proliferation (44). Tumor-derived exosomal lncRNAs have been indicated as signaling mediators that orchestrate the communications between tumor cells and macrophages in TME.…”

Metastatic breast cancer cells induce altered microglial morphology and electrical excitability in vivo

“…The spectrum of activated microglial phenotypes in brain tumours ranges from "classical" M1 proinflammatory cells capable of releasing proinflammatory cytokines and eliciting a T cell response, to "alternative" M2 anti-inflammatory cells which promote tumour growth, angiogenesis and invasion [21][22][23][24][25]. Thus, targeting the anti-inflammatory microglial population [26][27][28], and/or enhancing the activity of the proinflammatory population [29], may provide a new treatment approach for brain metastases. However, better models are required to improve understanding of the functional activity of microglia in the microenvironment around brain tumour cells.…”