Disseminated tumor cells (DTCs) shed from a primary tumor may lie dormant in distant tissues for long periods of time before they can be activated to form metastases. Recently work in our group has shown that (i) the engraftment of hematopoietic stem cells (HSC) and (ii) prostate cancer (PCa) metastasis to the marrow are dependent on many of the same molecules. In fact, we have recently demonstrated that metastatic PCa directly competes with HSC for occupancy of the niche. We have also developed technology and models that permits isolation of human DTCs from marrow using anti-human leukocyte antigens (HLA). Hypothesis: Molecules that induce HSC dormancy also induce dormancy of metastatic PCa cells and can be used to identify DTCs. The following aims are proposed: (1) Identify the differences between circulating tumor cells (CTCs) and successful DTCs. Sub Hypothesis: Dormant DTCs have different profiles from CTCs and dividing DTCs. We will determine the expression levels of receptors, known to regulate homing, lodging and growth, and gene expression profiling on CTCs and DTCs that will be obtained from our murine xenograft model. Then, these analyses will be repeated with CTCs and DTCs obtained from PCa patients. (2) Identify the specific subtype of DTCs that become dormant. Sub hypotheses: DTCs that become dormant have the capability to eventually form tumors. First, we will determine the frequency of tumorigenic cells in the dormant DTCs by implanting into immunocompromized mice. Next, we will determine the tumorogenic phenotype while determining if these cells also have the colony-forming ability and chemo-resistant ability. Finally, we will determine if we can manipulate dormant state of these cells with GAS6 (See Project 2) or IL-6 (See Project 3). (3) Determine the molecular mechanism that is critical for DTCs to become dormant. Sub hypotheses: The binding to annexin 2 (AnxaZ) is critical for DTCs to become dormant We have demonstrated that Anxa2 expressed by osteoblasts is a crucial molecule for the niche selection of PCa, This suggests that PCa obtain the signals from the niche through the Anxa2/Anxa2r axis. Therefore, we will determine if blocking Anxa2r on PCa prevents becoming dormant. In addition, we have observed that when PCa bind to Anxa2, the expression of Axl, the receptors for GAS6, is enhanced on the PCa. Thus, we will determine signaling pathway that is involved in the effects of Anxa2 on Axl induction. These findings will directly lend support to Project 2 which will determine how endosteal HSC niche regulates tumor dormancy, and Project 3 which focuses on what leads to activation of the dormant cells.

Public Health Relevance

In prostate cancer, tumor dormancy is a key event for a long-term survival of disseminated tumor cells (DTCs) in the distant tissues. Our proposed investigations will focus on fundamental mechanisms how DTCs become dormant in the bone marrow. The new insights derived from our investigations will be relevant to identify the phenotype of DTCs that is uniquely responsible for tumor relapse, and will lead to develop new traget therapies for metastatic tumors.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center--Cooperative Agreements (U54)
Project #
5U54CA163124-03
Application #
8567739
Study Section
Special Emphasis Panel (ZCA1-SRLB-3)
Project Start
Project End
Budget Start
2013-08-01
Budget End
2014-07-31
Support Year
3
Fiscal Year
2013
Total Cost
$152,240
Indirect Cost
$95,970
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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