Breast cancer has become a curable disease if it is diagnosed at an early stage;however, more than 90% of breast cancer deaths are still attributed to metastases and bone is the major distant organ of metastatic breast tumor growth. Therefore, it is of paramount importance to elucidate the exact pathological mechanism of bone metastasis to identify a specific therapeutic target for this devastating disease. The recent cancer stem cell theory, which still remains as a hypothesis, predicts that there is a distinct population of metastatic cells that have stem-like characteristics as well as invasive ability. Our preliminary data indicate that (i) cancer stem-like cells (CSCs) from highly metastatic cell lines express a high level of hyaluronan synthase gene 2 (HAS2) which is significantly correlated with patient metastasis-free survival, (ii) HAS2 in CSCs significantly activates the expression of PDGF-BB in tumor associated macrophage (TAM) through interaction of hyaluronic acid (HA) in CSCs and CD44 in TAM, which then activates the expression of FGF7 and FGF9 in bone niche cells followed by stimulating self-renewal of CSCs and (iii) the inhibitor of HAS2, 4MU, can block this vicious cycle in the bone niche and significantly suppress bone metastasis in vitro and in vivo. In the current grant application, we propose our novel hypotheses that (i) high expression of HA in CSCs facilitates a """"""""take-over"""""""" of pre- existing niche of hematopoietic stem cells (HSC) in the bone and activates TAM and mobilizes the bone niche, which in turn promotes self-renewal of CSC and (ii) a prodrug inhibitor for HAS2 can be used for preventive and therapeutic intervention of metastatic disease. To test these hypotheses, we will first examine the role of HAS2 of CSCs in bone metastasis in vivo and also test the efficacy of a novel """"""""pro- drug"""""""" of HAS2 inhibitor in our animal model of bone metastasis (Aim 1). We will also elucidate the mechanism by which HAS2 promotes self-renewal of CSC by mobilizing bone microenvironment in vitro (Aim 2). Furthermore, we will directly examine the clinical relevance of HAS2 in breast cancer metastasis and identify potential diagnostic/prognostic markers for bone metastasis (Aim 3). The ultimate goal of this project is to define the pathological process of bone metastasis and identify specific therapeutic and preventive targets for this devastating disease. We do believe that the proposed hypothesis, if proven to be valid, will present a novel paradigm to understand the pathological mechanism of bone metastasis which will significantly impact the treatment of breast cancer.

Public Health Relevance

More than 90% of deaths from breast cancer are still attributed to metastatic disease and bone is the major distant organ of the metastatic growth. Although the pathological process of tumor metastasis is as yet poorly understood, it is believed that metastasis is caused by a distinct population of tumor cells called cancer stem- like cells (CSCs). The current project aims at elucidating the exact molecular mechanism by which CSCs restructure the stem cell niche in the bone microenvironment in order to define novel therapeutic and preventive targets for this devastating disease. We also plan to develop and test a pro-drug to inhibit bone metastasis in our animal models.

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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Woodhouse, Elizabeth
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University of Mississippi Medical Center
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
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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
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