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.
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.
|de Groot, Amber E; Pienta, Kenneth J (2018) Epigenetic control of macrophage polarization: implications for targeting tumor-associated macrophages. Oncotarget 9:20908-20927|
|Roca, Hernan; Jones, Jacqueline D; Purica, Marta C et al. (2018) Apoptosis-induced CXCL5 accelerates inflammation and growth of prostate tumor metastases in bone. J Clin Invest 128:248-266|
|Wu, Amy; Liao, David; Kirilin, Vlamimir et al. (2018) Cancer dormancy and criticality from a game theory perspective. Cancer Converg 2:1|
|Park, Sun H; Keller, Evan T; Shiozawa, Yusuke (2018) Bone Marrow Microenvironment as a Regulator and Therapeutic Target for Prostate Cancer Bone Metastasis. Calcif Tissue Int 102:152-162|
|Singhal, Udit; Wang, Yugang; Henderson, James et al. (2018) Multigene Profiling of CTCs in mCRPC Identifies a Clinically Relevant Prognostic Signature. Mol Cancer Res 16:643-654|
|Lee, Eunsohl; Wang, Jingcheng; Jung, Younghun et al. (2018) Reduction of two histone marks, H3k9me3 and H3k27me3 by epidrug induces neuroendocrine differentiation in prostate cancer. J Cell Biochem 119:3697-3705|
|van der Toom, Emma E; Axelrod, Haley D; de la Rosette, Jean J et al. (2018) Prostate-specific markers to identify rare prostate cancer cells in liquid biopsies. Nat Rev Urol :|
|Roca, Hernan; McCauley, Laurie K (2018) Efferocytosis and prostate cancer skeletal metastasis: implications for intervention. Oncoscience 5:174-176|
|Chalfin, Heather J; Glavaris, Stephanie A; Malihi, Paymaneh D et al. (2018) Prostate Cancer Disseminated Tumor Cells are Rarely Detected in the Bone Marrow of Patients with Localized Disease Undergoing Radical Prostatectomy across Multiple Rare Cell Detection Platforms. J Urol 199:1494-1501|
|Axelrod, Haley D; Pienta, Kenneth J; Valkenburg, Kenneth C (2018) Optimization of Immunofluorescent Detection of Bone Marrow Disseminated Tumor Cells. Biol Proced Online 20:13|
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