Bone metastases are the major contributing factors to prostate cancer (PCa) morbidity and mortality. PCa bone metastases are uniquely osteoblastic and characterized by new bone formation, which promotes tumor growth in bone. Thus, bi-directional interaction between the PCa cells and their mis-induced bone plays a critical role in PCa progression in bone. It has been assumed that metastatic PCa induces new bone formation by stimulating the proliferation of osteoblasts in the bone marrow. However, we recently demonstrated that tumor-associated endothelial cells could give rise to osteoblasts through a little-appreciated process known as endothelial cell-to- osteoblast (EC-to-OSB) conversion, generating in the process EC-OSB hybrid cells with unique properties. Our studies showed that tumor-induced EC-to-OSB conversion is one mechanism that leads to osteoblastic bone metastasis of PCa. This new insight into the surprising bone-forming role of EC-OSB hybrid cells in PCa bone metastasis provides a novel rationale to target these cells in the tumor microenvironment. We hypothesize that tumor-induced EC-to-OSB conversion generates EC-OSB hybrid cells, which provide paracrine factors to support metastatic PCa growth in bone. Our objective is to target EC-OSB hybrid cells for improving therapy for bone metastasis. We will:
Aim 1. Determine the mechanisms underlying endothelial cell-to-osteoblast (EC-to-OSB) transition. EC-to-OSB conversion requires both the inhibition of angiogenesis and activation of osteoblastogenesis pathways in endothelial cells. Our preliminary results indicate that BMP4 activates the Notch-Hey1 pathway to inhibit angiogenesis and the p38MAPK-?-catenin-OSX pathway to stimulate osteogenesis. We will examine how BMP4 integrates these two pathways to reprogram the endothelial cells.
Aim 2. Identify EC-OSB hybrid cell secreted factors (EC-OSB factors) that promote PCa progression. EC-OSB hybrid cell secretome was examined by both iTRAQ (protein) and RNAseq (gene) analyses. Tenascin C was identified along with CTGF and versican, which together may constitute an ?EC-to-OSB signature?. We will investigate the effects of these EC-OSB factors on PCa cell activity in vitro and in vivo. The ?EC-OSB signature? will also be tested as biomarkers for osteoblastic bone metastasis using clinical samples.
Aim 3. Develop strategies that target EC-OSB hybrid cells to improve therapy outcomes for PCa bone metastasis. The EC- OSB hybrid cells may contribute to de novo therapy resistance described previously. We will examine whether we can improve therapy outcomes for PCa bone metastasis by combining cabozantinib or cabazitaxel (targets PCa tumor) with Rad-223 (targets EC-OSB hybrid cells).
Aim 4. Determine whether EC-to-OSB transition occurs in normal bone and the fraction of EC-OSB hybrid cells in tumor-induced bone. We generated a new Double Reporter Mice (col1?1-GFP/Tie2-cre/Rosa-tdTomato), in which EC are RFP+, OSB are GFP+, and EC-OSB are RFP+/GFP+, to examine whether EC-OSB hybrid cells are involved in normal bone development and their fraction in tumor-induced bone.

Public Health Relevance

Prostate cancer is dominated by complications arising from bone metastasis, which often has a lethal outcome. This proposal tests the novel concept that inhibition of endothelial-osteoblast hybrid cells in combination with chemotherapy will decrease prostate tumor growth in bone. The successful outcome of our studies will improve the quality of life and prolong the survival of patients with bone metastasis.

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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Watson, Joanna M
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University of Texas MD Anderson Cancer Center
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Pan, Tianhong; Lin, Song-Chang; Yu, Kai-Jie et al. (2018) BIGH3 Promotes Osteolytic Lesions in Renal Cell Carcinoma Bone Metastasis by Inhibiting Osteoblast Differentiation. Neoplasia 20:32-43
Yu-Lee, Li-Yuan; Yu, Guoyu; Lee, Yu-Chen et al. (2018) Osteoblast-Secreted Factors Mediate Dormancy of Metastatic Prostate Cancer in the Bone via Activation of the TGF?RIII-p38MAPK-pS249/T252RB Pathway. Cancer Res 78:2911-2924
Lin, Song-Chang; Yu-Lee, Li-Yuan; Lin, Sue-Hwa (2018) Osteoblastic Factors in Prostate Cancer Bone Metastasis. Curr Osteoporos Rep 16:642-647
Yu, Kai-Jie; Li, Jeffrey K; Lee, Yu-Chen et al. (2017) Cabozantinib-induced osteoblast secretome promotes survival and migration of metastatic prostate cancer cells in bone. Oncotarget 8:74987-75006
Bilen, Mehmet Asim; Pan, Tianhong; Lee, Yu-Chen et al. (2017) Proteomics Profiling of Exosomes from Primary Mouse Osteoblasts under Proliferation versus Mineralization Conditions and Characterization of Their Uptake into Prostate Cancer Cells. J Proteome Res 16:2709-2728
Lin, Song-Chang; Lee, Yu-Chen; Yu, Guoyu et al. (2017) Endothelial-to-Osteoblast Conversion Generates Osteoblastic Metastasis of Prostate Cancer. Dev Cell 41:467-480.e3
Weiderhold, Kimberly N; Fadri-Moskwik, Maria; Pan, Jing et al. (2016) Dynamic Phosphorylation of NudC by Aurora B in Cytokinesis. PLoS One 11:e0153455
Sun, Sheng; Sun, Le; Zhou, Xi et al. (2016) Phosphorylation-Dependent Activation of the ESCRT Function of ALIX in Cytokinetic Abscission and Retroviral Budding. Dev Cell 36:331-43
Satcher, Robert L; Pan, Tianhong; Bilen, Mehmet A et al. (2015) Cadherin-11 endocytosis through binding to clathrin promotes cadherin-11-mediated migration in prostate cancer cells. J Cell Sci 128:4629-41
Lee, Yu-Chen; Gajdosik, Martina Srajer; Josic, Djuro et al. (2015) Secretome analysis of an osteogenic prostate tumor identifies complex signaling networks mediating cross-talk of cancer and stromal cells within the tumor microenvironment. Mol Cell Proteomics 14:471-83

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