The common occurrence and serious outcome of prostate cancer (PCa) skeletal metastases has risen to the forefront of public concern and subsequently the NCI. In the first three years of this program award, we have addressed this important issue, resulting in over 50-grant-related publications. In the current competitive renewal, we continue to attack this problem by combining leading expertise in PCa research and bone metabolism. The ultimate goal is to define the cellular and molecular mechanisms that surround PCa skeletal metastases so as to set the groundwork for translation into clinical applications. The central theme of this Program is that there is crosstalk between PCa cells and the bone microenvironment that foster the development and progression of PCa metastasis. This crosstalk promotes the ability of PCa cells to migrate, attach, and manipulate the cells in bone thus enhancing the tumor's capacity to alter the bone microenvironment to render it conducive to tumor growth. To expand on this theme the Program encompasses closely interrelated hypotheses of four scientific projects supported by three cores. Project 1 explores the novel concept that the similar to an endocrine organ, the primary PCa modulates the distant bone marrow, in part through production of CCLZ, to make it conducive for receiving metastatic PCa cells;Project 2 examines the exciting idea that PCa cells co-opt the hematopoietic stem cell (HSC) niche in the bone marrow;Project 3 explores the unexpected role of the Wnt inhibitor Dickopff as a molecular switch that promotes the osteoblastic phenotype of PCa;and, Project 4 investigates the novel hypothesis that PCa, through PTHrP, modulates osteoblasts and HSCs leading to angiogenesis in the bone microenvironment that promotes PCa progression. These projects will be supported by three integral cores: Core A (Administration) that will coordinate reporting, evaluation, and committee activities, facilitate interactions among the projects and provide biostatistical support;Core B (Animal) provides mouse models and imaging and assistance with their use and Core C (Bone) provides expertise with bone histology processing and interpretation. This combination of investigators, projects and cores result in a highly synergistic Program that will continue to provide cutting-edge research on PCa bone metastases.

Public Health Relevance

Prostate cancer (PCa) is the most common cancer of American men and the second leading cause of cancer-related death. When men die from PCa, it is almost always accompanied by the painful and debilitating spread of cancer to the skeleton. Our Program is directed to understand how the cancer spreads to and thrives in the skeleton so that we can develop method to prevent or treat the spread of PCa to the bone.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Special Emphasis Panel (ZCA1-RPRB-O (J1))
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Mohla, Suresh
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
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Tang, Yi; Feinberg, Tamar; Keller, Evan T et al. (2016) Snail/Slug binding interactions with YAP/TAZ control skeletal stem cell self-renewal and differentiation. Nat Cell Biol 18:917-29
Jung, Younghun; Decker, Ann M; Wang, Jingcheng et al. (2016) Endogenous GAS6 and Mer receptor signaling regulate prostate cancer stem cells in bone marrow. Oncotarget 7:25698-711
Day, Kathleen C; Lorenzatti Hiles, Guadalupe; Kozminsky, Molly et al. (2016) HER2 and EGFR overexpression support metastatic progression of prostate cancer to bone. Cancer Res :
Yumoto, Kenji; Eber, Matthew R; Wang, Jingcheng et al. (2016) Axl is required for TGF-β2-induced dormancy of prostate cancer cells in the bone marrow. Sci Rep 6:36520
Cackowski, Frank C; Eber, Matthew R; Rhee, James et al. (2016) Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy. J Cell Biochem :
Chen, F; Dai, Z; Kang, Y et al. (2016) Effects of zoledronic acid on bone fusion in osteoporotic patients after lumbar fusion. Osteoporos Int 27:1469-76
Amend, Sarah R; Roy, Sounak; Brown, Joel S et al. (2016) Ecological paradigms to understand the dynamics of metastasis. Cancer Lett 380:237-42
van der Toom, Emma E; Verdone, James E; Pienta, Kenneth J (2016) Disseminated tumor cells and dormancy in prostate cancer metastasis. Curr Opin Biotechnol 40:9-15
Amend, Sarah R; Valkenburg, Kenneth C; Pienta, Kenneth J (2016) Murine Hind Limb Long Bone Dissection and Bone Marrow Isolation. J Vis Exp :
Lee, Eunsohl; Wang, Jingcheng; Yumoto, Kenji et al. (2016) DNMT1 Regulates Epithelial-Mesenchymal Transition and Cancer Stem Cells, Which Promotes Prostate Cancer Metastasis. Neoplasia 18:553-66

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