Bone metastasis is the leading cause of morbidity and mortality in prostate cancer (pc) patients. MT1-MMP (membrane type 1-MMP, also known as MMP-14) is highly expressed in tumor cells in human pc bone metastases. MT1-MMP has been shown to promote expansion of the metastatic deposit and the osteolytic side of the bone response. MT1-MMP is also responsible for the release (shedding) of RANKL (receptor activator of nuclear factor-kappa B ligand), an osteoclastogenic factor which is crucial for the initiation of the osteoclastic response. However, the biochemical mechanisms by which MT1-MMP releases RANKL and the extent to which RANK signaling in tumor cells promotes progression of the metastatic deposit have not been characterized. Also, the relative effects of RANKL derived from tumor cells vs. bone cells is unknown. Herein, we hypothesize that tumor-derived MT1-MMP cleaves membrane-bound RANKL (mRANKL) on tumor cells. This shedding event yields a soluble form of RANKL (sRANKL) that contributes to the progression of the metastatic deposit by activating specific RANK-associated cell signaling pathways in cancer cells and bone cells. To further understand this process, we propose to (1) investigate the structural basis of MT1-MMP shedding of mRANKL and identify MT1-MMP/mRANKL complexes at the surface of pc cells;(2) investigate the MT1-MMP - RANKL - RANK signaling axis in prostate cancer cells;and (3) define the contributions of tumor-derived RANKL and RANK to intraosseous tumor growth and bone remodeling in MT1-MMP-driven tumors. This proposal will use a variety of biochemical and cellular approaches as well as animal models of bone metastasis.
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