Prostate cancers (PCa) have an astonishing ability to disseminate, invade and survive in the bone marrow. Once there, disseminated tumor cells (DTCs) may lie dormant for years. How dormancy of DTCs is established, how it is maintained, and how DTCs escape from dormancy remains unknown. Hematopoietic stem cells (HSCs), like DTCs, are largely quiescent In the marrow. HSC quiescence is regulated by a region in marrow termed the 'niche', that is comprised of osteoblasts, endothelial cells and other elements. Recent work demonstrates that when HSCs bind to proteins expressed by niche osteoblasts (annexin 2 or AX2), they increase their expression of the tyrosine kinase receptor AXL (from the Greek word 'anexelekto,' or uncontrolled). Sequentially, AXL binds to growth arrest-specific 6 (GAS6), which is secreted in the marrow niche by osteoblasts. In many systems GAS6 inhibits cellular proliferation, promotes survival and increases resistance to chemotherapy. We have recentiy show that; (i) PCa DTCs target the HSC niche during metastasis (submitted) (ii) when PCa cells bind to niche osteoblasts or components of the niche (AX2), they increase expression of AXL, (iii) GAS6 inhibits PCa cell growth, (iv) GAS6 protects PCa cells from apoptosis, (v) GAS6 confers resistance of PCa cells to chemotherapy. These data suggest that once DTCs enter the niche, interactions between GAS6 and its receptors regulates dormancy of DTCs and resistance to chemotherapies that target proliferating cells. Our central hypothesis is that GAS6 regulates dormancy of PCa bone metastases The proposed aims will demonstrate the extent to which GAS6 signaling determines whether DTCs remain quiescent or proliferate in bone Aim 1: Determine the extent to which GAS6 induces quiescence of PCa cells in the HSC 'niche'. Sub hypothesis: Niche produced GAS6 is essential for establishing dormancy.
Aim 2 : Define the role that autocrine production of GAS6 regulates dormancy of PCa in the niche Sub hypothesis: PCa themselves express GAS6 which limits growth in an autocrine fashion. We hypothesize that dormancy is established by cells that maintain this activity - but that it is eventually lost by cells that undergo metastatic growth.
Aim 3 : Define the role that GAS6 signaling plays in regulating resistance of PCa to chemotherapy in the HSC 'niche'. Sub hypothesis: Dormant PCa cells are resistant to chemotherapy.

Public Health Relevance

These investigations focus on fundamental mechanisms related to tumor cell dormancy of PCa bone metastasis. We are confident that our observations are relevant to a more complete understanding prostate cancer skeletal disease. That new insights derived from these studies will lead to the development of innovative strategies to minimize the morbidity and mortality associated with bone metastatic prostate cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-SRLB-3 (O1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Michigan Ann Arbor
Ann Arbor
United States
Zip Code
Park, Sun H; Eber, Matthew R; Tsuzuki, Shunsuke et al. (2017) Adeno-associated virus serotype rh10 is a useful gene transfer vector for sensory nerves that innervate bone in immunodeficient mice. Sci Rep 7:17428
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
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
Shiozawa, Yusuke; Berry, Janice E; Eber, Matthew R et al. (2017) Correction: The marrow niche controls the cancer stem cell phenotype of disseminated prostate cancer. Oncotarget 8:38075
Decker, A M; Cackowski, F C; Jung, Y et al. (2017) Biochemical Changes in the Niche Following Tumor Cell Invasion. J Cell Biochem 118:1956-1964
Shiozawa, Yusuke; Berry, Janice E; Eber, Matthew R et al. (2016) The marrow niche controls the cancer stem cell phenotype of disseminated prostate cancer. Oncotarget 7:41217-41232
Amend, Sarah R; Valkenburg, Kenneth C; Pienta, Kenneth J (2016) Murine Hind Limb Long Bone Dissection and Bone Marrow Isolation. J Vis Exp :

Showing the most recent 10 out of 66 publications