The overall goal of the Sanderson Lab is to determine the role of the heparan sulfate / heparanase axis in regulating cancer and to use this knowledge to develop new anti-cancer therapies. The immediate goal of this project is to define heparanase regulation of the metastatic cascade using multiple myeloma as a model cancer. Myeloma is a devastating cancer that thrives in the bone marrow and disseminates throughout the skeleton leading to severe pain, poor quality of life and eventual death of the patient. Although it is the metastatic nature of this cancer that kills patients, unfortunately, the mechanisms regulating metastasis in myeloma are unknown. The key to improving patient treatment lies in developing a mechanistic understanding of myeloma metastasis and testing new inhibitors to block tumor dissemination. Using in vivo models, we have shown that the heparan sulfate degrading enzyme heparanase is a key driver of myeloma growth, angiogenesis, osteolysis and metastasis. Importantly, we also discovered that enzymatically active heparanase is present within the bone marrow of myeloma patients and it correlates with poor patient prognosis. Striking new data from our lab indicates that heparanase acts as a master regulator of metastasis in myeloma by upregulating expression of several genes including VEGF, MMP-9 and uPA/uPAR that work in concert to drive metastasis. We hypothesize that heparanase acts as a key mediator of myeloma metastasis by promoting initial intravasation of tumor cells into the blood at the primary tumor site and by preparing pre-metastatic niches in bone that facilitate tumor cell homing and growth. Given these two critical functions in metastasis, we further hypothesize that heparanase inhibitors in combination with other anti-myeloma compounds will provide a novel and potent therapeutic approach to this deadly disease.
Aim 1 will examine the importance of heparanase in driving myeloma metastasis, the stage(s) of metastasis where heparanase exerts its effects and the influence of heparanase on establishing pre-metastatic niches in the bone marrow.
Aim 2 will test a novel heparanase inhibitor in for its anti- metastatic effects in vivo when administered either as a single agent or in combination with dexamethasone.
Heparanase is a protein made by cancer cells that plays a major role in helping them grow and spread throughout the body. This project is designed to reveal how heparanase functions and to test a new anti- heparanase drug to determine if it can block the spread of cancer.
|Stewart, Mark D; Sanderson, Ralph D (2014) Heparan sulfate in the nucleus and its control of cellular functions. Matrix Biol 35:56-9|
|Ramani, Vishnu C; Sanderson, Ralph D (2014) Chemotherapy stimulates syndecan-1 shedding: a potentially negative effect of treatment that may promote tumor relapse. Matrix Biol 35:215-22|
|Vlodavsky, Israel; Blich, Miry; Li, Jin-Ping et al. (2013) Involvement of heparanase in atherosclerosis and other vessel wall pathologies. Matrix Biol 32:241-51|
|Ramani, Vishnu C; Purushothaman, Anurag; Stewart, Mark D et al. (2013) The heparanase/syndecan-1 axis in cancer: mechanisms and therapies. FEBS J 280:2294-306|
|Vlodavsky, Israel; Iozzo, Renato V; Sanderson, Ralph D (2013) Heparanase: multiple functions in inflammation, diabetes and atherosclerosis. Matrix Biol 32:220-2|
|Ruan, Jian; Trotter, Timothy N; Nan, Li et al. (2013) Heparanase inhibits osteoblastogenesis and shifts bone marrow progenitor cell fate in myeloma bone disease. Bone 57:10-7|
|Thompson, Camilla A; Purushothaman, Anurag; Ramani, Vishnu C et al. (2013) Heparanase regulates secretion, composition, and function of tumor cell-derived exosomes. J Biol Chem 288:10093-9|
|Ramani, Vishnu C; Pruett, Pamela S; Thompson, Camilla A et al. (2012) Heparan sulfate chains of syndecan-1 regulate ectodomain shedding. J Biol Chem 287:9952-61|
|Purushothaman, Anurag; Hurst, Douglas R; Pisano, Claudio et al. (2011) Heparanase-mediated loss of nuclear syndecan-1 enhances histone acetyltransferase (HAT) activity to promote expression of genes that drive an aggressive tumor phenotype. J Biol Chem 286:30377-83|
|Ramani, Vishnu C; Yang, Yang; Ren, Yongsheng et al. (2011) Heparanase plays a dual role in driving hepatocyte growth factor (HGF) signaling by enhancing HGF expression and activity. J Biol Chem 286:6490-9|
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