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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center--Cooperative Agreements (U54)
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University of Michigan Ann Arbor
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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
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