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)
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
Jung, Younghun; Wang, Jingcheng; Lee, Eunsohl et al. (2015) Annexin 2-CXCL12 interactions regulate metastatic cell targeting and growth in the bone marrow. Mol Cancer Res 13:197-207
Cordeiro-Spinetti, Eric; Taichman, Russell S; Balduino, Alex (2015) The bone marrow endosteal niche: how far from the surface? J Cell Biochem 116:11-Jun
Roca, Hernan; Pande, Manjusha; Huo, Jeffrey S et al. (2014) A bioinformatics approach reveals novel interactions of the OVOL transcription factors in the regulation of epithelial - mesenchymal cell reprogramming and cancer progression. BMC Syst Biol 8:29
Axelrod, Haley; Pienta, Kenneth J (2014) Axl as a mediator of cellular growth and survival. Oncotarget 5:8818-52
Yumoto, Kenji; Berry, Janice E; Taichman, Russell S et al. (2014) A novel method for monitoring tumor proliferation in vivo using fluorescent dye DiD. Cytometry A 85:548-55
Yumoto, Kenji; Eber, Matthew R; Berry, Janice E et al. (2014) Molecular pathways: niches in metastatic dormancy. Clin Cancer Res 20:3384-9
Yang, Kimberline R; Mooney, Steven M; Zarif, Jelani C et al. (2014) Niche inheritance: a cooperative pathway to enhance cancer cell fitness through ecosystem engineering. J Cell Biochem 115:1478-85
Wan, Liling; Hu, Guohong; Wei, Yong et al. (2014) Genetic ablation of metadherin inhibits autochthonous prostate cancer progression and metastasis. Cancer Res 74:5336-47
Shiozawa, Yusuke; McGee, Samantha; Pienta, Michael J et al. (2013) Erythropoietin supports the survival of prostate cancer, but not growth and bone metastasis. J Cell Biochem 114:2471-8
Taichman, Russell S; Patel, Lalit R; Bedenis, Rachel et al. (2013) GAS6 receptor status is associated with dormancy and bone metastatic tumor formation. PLoS One 8:e61873

Showing the most recent 10 out of 18 publications