Interactions of the WNT and RANKL/OPG pathways in osteomimicry of prostate cancer

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In the process of skeletal metastasis it remains unclear how prostate cancer cells acquire an osteoblast-like phenotype (osteomimicry) and modulate osteogenesis. We will test the hypothesis whether WNT proteins, in particular WNT5A, promote tumor development and tumor cell osteomimicry and modulate osteoclast biology through receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG). Based on studies on RANKL/OPG and our recent findings that WNT proteins and RANKL are highly expressed in advanced prostate cancer, we will address three specific aims. (I) Define the WNT and RANKL/OPG profile of osteotropic prostate cancer cell lines and tissues during skeletal metastasis. (II) Analyze interactions between WNT and RANKL/OPG and the involved signaling pathways in the bone-tumor dialogue. We will employ co-culture models and assess specific factors from aim I by using knock-down and over-expression techniques. (III) To investigate the role of the WNT pathway in skeletal metastases, we will employ animal models. Osteoblastic and osteolytic tumor cell lines with defined WNT profiles will be fluorescent-labeled and injected into Col1α1-IFP-transgenic mice. Skeletal tumor progression and altered osteoblastic function will be monitored in vivo using molecular imaging and analyzed by histology and gene expression analysis. These studies may identify key signals of skeletal metastasis which could be targeted for diagnosis and therapy.