The tumor microenvironment has emerged as a major regulator of tumor growth and progression. The long-term goal of the Sanderson lab is to determine how tumor-host cell interactions mediated by heparan sulfate and the enzyme heparanase regulate the tumor microenvironment and to use that knowledge to design new cancer therapies. We have shown that heparan sulfate proteoglycans and heparanase promote tumor growth and metastasis of multiple myeloma and breast tumors, two tumors that home to and grow within bone. Our hypothesis is that heparan sulfate drives tumor growth by concentrating heparin-binding growth factors (e.g., FGF-2, VEGF, HGF) within the tumor microenvironment and promoting interactions of these growth factors with their high affinity receptors. Thus, interfering with heparan sulfate function has the potential to attenuate numerous signaling pathways important in tumor growth and metastasis. Our current experimental focus is two-fold. First, we are examining how enzymes that modify heparan sulfate such as heparanase alter tumor behavior and promotes an aggressive tumor phenotype. We have recently discovered that this occurs, at least in part, via heparanase regulation of tumor secreted exosomes. These small vesicles contain proteins and nucleic acids that can be transferred horizontally to other cells within the tumor microenvironment and beyond and thus act as important mediators of intercellular communication. Second, we are developing novel heparanase inhibitors and testing them as potential anti-cancer drugs. This work will lead to a better understanding of the tumor microenvironment and how it can be disrupted to block tumor growth. Our work is currently funded by the National Institutes of Health.