The long-term objective of this work is to determine how heparan sulfate proteoglycans on the cell surface regulate tumor cell behavior and to use this knowledge for developing novel therapies for cancer. Myeloma cells have been used as a model to demonstrate that expression of syndecan-1 has a dramatic impact on tumor cell behavior by promoting cell-cell and cell-matrix adhesion, inhibiting cell invasion, suppressing cell growth and inducing apoptosis. Together, these data indicate that syndecan-1 acts as a powerful tumor suppressor. Three striking new discoveries made during the previous funding period support the hypothesis that syndecan-1 function on tumor cells is tightly regulated by interactions with other effector molecules. The immediate goal is to identify these molecules and to determine how they regulate syndecan-1 function. This will be accomplished through three specific aims.
Aim 1. Studies using mutated and chimeric proteoglycans expressed in tumor cells indicate that a region of the ectodomain core protein of syndecan-1 interacts with other cell surface molecules (co-anchors) to promote the inhibition of cell invasion and cell spreading. The region of the core protein mediating these interactions will be determined, the co-anchor molecules isolated and characterized, and their role in regulating syndecan-1 function explored.
Aim 2. Recent work demonstrates that syndecan-1 localizes specifically to the uropod (training edge) of polarized myeloma cells and that this targeting is dependent on the presence of both heparan sulfate chains and the cytoplasmic domain of syndecan-1. This model will be exploited to examine the molecular interactions that link syndecan-1 to the cytoskeleton and to determine how heparan sulfate located on the cell surface can regulate targeting.
Aim 3. In direct contrast to cell surface syndecan-1 which inhibits cell invasion, new studies show that soluble syndecan-1 promotes cell invasion. Thus, enzymatic remodeling of syndecan-1 may have a dramatic impact on tumor cell behavior by shifting syndecan-1 from an inhibitor of metastasis to a promoter of metastasis. Studies will characterize the effects on tumor cells resulting from proteolytic shedding of syndecan-1 and from the degradation of heparan sulfate chains by heparanase. Insight gained from these studies will be used to design new therapeutic strategies aimed at halting tumor growth and metastasis.
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