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// Younghun Jung 1 , Ann M. Decker 1 , Jingcheng Wang 1 , Eunsohl Lee 1 , Lulia A. Kana 1 , Kenji Yumoto 1 , Frank C. Cackowski 1, 2 , James Rhee 1 , Peter Carmeliet 3, 4 , Laura Buttitta 5 , Todd M. Morgan 6 , Russell S. Taichman 1 1 Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA 2 Department of Internal Medicine, Division of Hematology and Oncology, University of Michigan School of Medicine, Ann Arbor, MI, USA 3 Laboratory of Angiogenesis and Vascular Metabolism, Vesalius Research Center (VRC), VIB, K.U. Leuven, Belgium 4 Laboratory of Angiogenesis and Vascular Metabolism, Department of Oncology, K.U. Leuven, Belgium 5 Department of Molecular, Cellular and Developmental Biology, University of Michigan, Ann Arbor, MI, USA 6 Department of Urology, University of Michigan School of Medicine, Ann Arbor, MI, USA Correspondence to: Russell S. Taichman, e-mail: rtaich@umich.edu Keywords: endogenous GAS6, Mer, prostate cancer, cancer stem cells, bone marrow Received: December 01, 2015 Accepted: March 07, 2016 Published: March 25, 2016 ABSTRACT GAS6 and its receptors (Tryo 3, Axl, Mer or “TAM”) are known to play a role in regulating tumor progression in a number of settings. Previously we have demonstrated that GAS6 signaling regulates invasion, proliferation, chemotherapy-induced apoptosis of prostate cancer (PCa) cells. We have also demonstrated that GAS6 secreted from osteoblasts in the bone marrow environment plays a critical role in establishing prostate tumor cell dormancy. Here we investigated the role that endogenous GAS6 and Mer receptor signaling plays in establishing prostate cancer stem cells in the bone marrow microenvironment. We first observed that high levels of endogenous GAS6 are expressed by disseminated tumor cells (DTCs) in the bone marrow, whereas relatively low levels of endogenous GAS6 are expressed in PCa tumors grown in a s.c. setting. Interestingly, elevated levels of endogenous GAS6 were identified in putative cancer stem cells (CSCs, CD133+/CD44+) compared to non-CSCs (CD133–/CD44–) isolated from PCa/osteoblast cocultures in vitro and in DTCs isolated from the bone marrow 24 hours after intracardiac injection. Moreover, we found that endogenous GAS6 expression is associated with Mer receptor expression in growth arrested (G 1 ) PCa cells, which correlates with the increase of the CSC populations. Importantly, we found that overexpression of GAS6 activates phosphorylation of Mer receptor signaling and subsequent induction of the CSC phenotype in vitro and in vivo . Together these data suggest that endogenous GAS6 and Mer receptor signaling contribute to the establishment of PCa CSCs in the bone marrow microenvironment, which may have important implications for targeting metastatic disease.