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 nine years of this program award, we have addressed this important issue, resulting in over 135-grant-related publications and set groundwork for several clinical trials. In the current competitive renewal, we further attack this problem by combining leading expertise in PCa research and bone biology. The ultimate goal is to define the cellular and molecular mechanisms that surround PCa skeletal metastases to facilitate translation into clinical application. The central theme of this Program is that there is crosstalk between PCa cells and the bone microenvironment that fosters the development and progression of PCa metastasis. This crosstalk promotes the ability of PCa cells to alter the bone microenvironment and render it fertile for 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 ability of tumor-associated macrophages (TAMs) to induce PCa cells to undergo epithelial to mesenchymal transition (EMT) is a key mediator of bone metastasis; Project 2 examines the exciting idea that the hematopoietic stem cell (HSC) niche induces disseminated tumor cells (DTCs) to adopt a primitive, phenotype capable of existing in a chemoresistant/dormant state, with the capacity for long-term survival and potential to develop into overt bone metastases; Project 3 explores the surprising role of primary PCa microvesicles in inducing a metabolic state in the distant marrow microenvironment that favors PCa growth; and Project 4 investigates the novel hypothesis that bone marrow macrophages support PCa growth in bone via phagocytosis/efferocytosis of apoptotic tumor cells. These projects will be supported by three integral cores: Core A (Administration) that will coordinate reporting, evaluation, and advisor 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, interpretation, and procurement of bone marrow elements. This combination of investigators, projects and cores result in a highly synergistic Program that will continue to provide cutting-edge research and leadership in the field of PCa skeletal 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 methods to prevent or treat the spread of PCa to the bone.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA093900-13
Application #
9312747
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (J1))
Program Officer
Woodhouse, Elizabeth
Project Start
2001-12-01
Project End
2020-05-31
Budget Start
2017-06-01
Budget End
2018-05-31
Support Year
13
Fiscal Year
2017
Total Cost
$1,510,770
Indirect Cost
$458,616
Name
University of Michigan Ann Arbor
Department
Urology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Park, Sun H; Keller, Evan T; Shiozawa, Yusuke (2017) Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis. Calcif Tissue Int :
Farhat, A; Jiang, D; Cui, D et al. (2017) An integrative model of prostate cancer interaction with the bone microenvironment. Math Biosci 294:1-14
de Groot, Amber E; Roy, Sounak; Brown, Joel S et al. (2017) Revisiting Seed and Soil: Examining the Primary Tumor and Cancer Cell Foraging in Metastasis. Mol Cancer Res 15:361-370
Zarif, Jelani C; Yang, Weiming; Hernandez, James R et al. (2017) The Identification of Macrophage-enriched Glycoproteins Using Glycoproteomics. Mol Cell Proteomics 16:1029-1037
Parsana, Princy; Amend, Sarah R; Hernandez, James et al. (2017) Identifying global expression patterns and key regulators in epithelial to mesenchymal transition through multi-study integration. BMC Cancer 17:447
Decker, Ann M; Jung, Younghun; Cackowski, Frank C et al. (2017) Sympathetic Signaling Reactivates Quiescent Disseminated Prostate Cancer Cells in the Bone Marrow. Mol Cancer Res 15:1644-1655
Day, Kathleen C; Lorenzatti Hiles, Guadalupe; Kozminsky, Molly et al. (2017) HER2 and EGFR Overexpression Support Metastatic Progression of Prostate Cancer to Bone. Cancer Res 77:74-85
Cackowski, Frank C; Eber, Matthew R; Rhee, James et al. (2017) Mer Tyrosine Kinase Regulates Disseminated Prostate Cancer Cellular Dormancy. J Cell Biochem 118:891-902
Koh, A J; Sinder, B P; Entezami, P et al. (2017) The skeletal impact of the chemotherapeutic agent etoposide. Osteoporos Int 28:2321-2333
Jiang, Yuan; Dai, Jinlu; Yao, Zhi et al. (2017) Abituzumab Targeting of ?V-Class Integrins Inhibits Prostate Cancer Progression. Mol Cancer Res 15:875-883

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