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; 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
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 :
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
Dai, Jinlu; Hensel, Janine; Wang, Ning et al. (2016) Mouse models for studying prostate cancer bone metastasis. Bonekey Rep 5:777
Amend, Sarah R; Pienta, Kenneth J (2015) Ecology meets cancer biology: the cancer swamp promotes the lethal cancer phenotype. Oncotarget 6:9669-78
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

Showing the most recent 10 out of 48 publications