A distinct feature of prostate cancer (PCa) with lethal potential is the ability of tumor cells to survive in a castrated environment and develop metastases in bone with a bone-forming phenotype. We recently demonstrated that PCa-induced aberrant bone overgrowth 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 is generally assumed that the metastatic PCa cells induce new bone formation by stimulating the proliferation of resident osteoblasts in the bone marrow. However, histopathological analyses of human bone metastasis specimens showed that woven bone was not from the adjacent bone surface. Thus, the origin of cells that were converted into osteoblasts by PCa is yet to be determined. Our objective is to identify the cell origin for the PCa-induced ectopic bone formation in PCa bone metastasis. While osteoblastic PCa bone metastasis is prevalent in the clinical setting, there is a lack of osteogenic PCa models for PCa bone metastasis study. Our xenograft core has recently successfully generated a bone forming PCa xenograft MDA-PCa-118b (PCa-118b) from a patient sample, providing us with a model to decipher the mechanism of PCa-induced bone formation. Using this xenograft, our preliminary results showed that (1) PCa-118b recruits mouse stromal cells into the tumors and converts them into osteoblasts;(2) Osteoblasts in PCa-118b also co-express the endothelial cell marker Tie2;(3) PCa-118b secretes factors, including BMP4 and TGF?2, which have been shown to promote endothelial-to-mesenchyme transition (EndMT);(4) BMP4 or TGF?2 are able to convert endothelial cells to express osterix (OSX), an osteoblast- specific transcription factor;and (5) In human PCa bone metastasis specimens, we detected stromal cells that co-express osteoblast and endothelial cell markers, osteocalcin and Tie2, respectively. Thus, we hypothesize that mis-induced bone in PCa bone metastasis originates from endothelial cells that were induced by PCa- secreted factors to undergo EndMT and osteoblastogenesis to form osteoblasts (OSB). The EndMT/OSB conversion leads to bone overgrowth that supports PCa progression in bone.
The Specific Aims are:
Aim 1. Identify tumor-secreted factors that induce EndMT/OSB in PCa bone metastasis. We will determine a minimal set of the secretory factors together with BMP4 and TGF?2 that are involved in inducing EndMT/OSB.
Aim 2. Determine how BMP4 and TGF?2 regulate the signal transduction and transcriptional program of endothelial cells during EndMT/OSB. RNA-seq and ChIP-seq will be used to identify the transcriptional network.
Aim 3. Determine whether blocking PCa-induced EndMT/OSB inhibits osteoblastic bone metastasis in vivo.
Aim 4. Examine the clinical relevance of EndMT/OSB in human PCa bone metastasis. Impact. The endothelial origin of osteoblasts will allow for strategies to target the key steps of the EndMT/OSB conversion for suppression of aberrant bone formation and thus, PCa progression in bone.

Public Health Relevance

The objective of this study is to delineate the mechanism of prostate cancer-induced aberrant bone formation in bone metastasis. Our work has identified that endothelial cells may be converted into osteoblasts by factors secreted by prostate cancer cells. This study will provide candidate targets for inhibiting prostate tumor growth in bone.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA174798-02
Application #
8641679
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Woodhouse, Elizabeth
Project Start
2013-04-01
Project End
2018-03-31
Budget Start
2014-04-01
Budget End
2015-03-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Texas MD Anderson Cancer Center
Department
Pathology
Type
Hospitals
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77030
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
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, 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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