Approximately 20-30% of patients with metastatic breast cancer develop brain metastasis, which is almost always fatal, and the median survival time of these patients is only few months. This observation is particularly imminent for patients with triple negative tumors. Ironically, recent advancement in chemotherapy has further increased the incidence of brain metastasis because most therapeutic agents cannot effectively penetrate the BBB and tumor cells find the brain as a sanctuary. Therefore, it is of paramount importance to elucidate the molecular mechanism involved in the metastatic process in order to define a specific therapeutic target. The recent cancer stem cell theory predicts that metastasis initiating cells (MIC) are by definition cancer stem-like cells (CSC). However, how MICs adapt themselves or passively generate a niche in the brain is a critical question. We have recently found that (i) brain MICs highly express the key inflammatory cytokine, IL-1?, which activates astrocytes, (ii) the secreted IL-1? up-regulates Jagged1, a Notch ligand, in the reactivated astrocytes, which in turn activates Notch signaling in MICs, (iii) IL-1? also mobilizes a microRNA network by activating miR301 and miR629, (iv) miR301 and miR629 are secreted from cancer cells as exosomes and suppress VHL expression, which results in HIF-1 and VEGF-D activation in astrocytes, and (v) VEGF-D then promotes MIC self-renewal. Based on these preliminary data, we hypothesize that brain MICs secrete IL-1?, which up-regulates Notch ligand expression in astrocytes and also stimulates the release of exosomal miR301/miR629 from the tumor cells that together activate cancer associated astrocytes, thereby, promoting MIC self-renewal. We also hypothesize that the secreted exosomes can serve as biomarkers for brain metastasis at an early stage and that a BBB-permeable and thermo-activatable pro-drugs can suppress brain metastasis progression by blocking IL-1? and Notch signaling. To test these hypotheses, we will first elucidate the roles of exosomal microRNAs in the metastatic niche generation in the brain (Aim 1). We will also define the role of IL1?-mediated activation of a microRNA network and Notch pathway in self-renewal of MICs in brain metastasis (Aim 2). We will then examine the efficacy of a BBB-permeable and thermo-activatable pro-drug on brain metastasis (Aim 3). Our study is highly innovative in that (i) we have identified the critical role of the brain microenvironment, particularly astrocytes, in the progression of MIC self- renewal, (ii) we showed that IL-1? also promote the secretion of exosomal microRNAs (miR301/miR629), which act as messengers for cell-cell communications in the stem cell niche, (iii) we will explore whether these exosomal microRNAs can be used as biomarkers for early diagnosis of brain metastasis, (iv) we will develop an innovative IL1RA pro-drug to target both tumor and microenvironmental cells in the brain. We believe that the outcome of our study will provide a paradigm shift in our current understanding of the pathology of brain metastasis and also have a significant impact on early detection of brain metastasis as well as on future treatments for this devastating disease.

Public Health Relevance

The incidence of brain metastasis of breast cancer is increasing at an alarming rate and this is particularly obvious in triple negative cancer. However, the pathological mechanism by which breast cancer cells grow in the brain, which has a totally different microenvironment from the primary tumor, is poorly understood. This project is designed to define critical factors and pathways that generate the niche for the metastasis initiating cells and to clarify how this niche promotes their growth in the brain. The overall goalof the project is to identify specific biomarkers that can be used for early detection of brain metastasis and also to develop target specific pro-drugs for brain metastatic disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Microenvironment Study Section (TME)
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Snyderwine, Elizabeth G
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Wake Forest University Health Sciences
Schools of Medicine
United States
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Xing, Fei; Liu, Yin; Wu, Shih-Ying et al. (2018) Loss of XIST in Breast Cancer Activates MSN-c-Met and Reprograms Microglia via Exosomal miRNA to Promote Brain Metastasis. Cancer Res 78:4316-4330
Wu, Kerui; Xing, Fei; Wu, Shih-Ying et al. (2017) Extracellular vesicles as emerging targets in cancer: Recent development from bench to bedside. Biochim Biophys Acta Rev Cancer 1868:538-563
Wu, Shih-Ying; Watabe, Kounosuke (2017) The roles of microglia/macrophages in tumor progression of brain cancer and metastatic disease. Front Biosci (Landmark Ed) 22:1805-1829
Sharma, Sambad; Xing, Fei; Liu, Yin et al. (2016) Secreted Protein Acidic and Rich in Cysteine (SPARC) Mediates Metastatic Dormancy of Prostate Cancer in Bone. J Biol Chem 291:19351-63
Wu, Kerui; Sharma, Sambad; Venkat, Suresh et al. (2016) Non-coding RNAs in cancer brain metastasis. Front Biosci (Schol Ed) 8:187-202
Xing, Fei; Liu, Yin; Sharma, Sambad et al. (2016) Activation of the c-Met Pathway Mobilizes an Inflammatory Network in the Brain Microenvironment to Promote Brain Metastasis of Breast Cancer. Cancer Res 76:4970-80