Defining mechanisms of extracellular communication for cancer therapy

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DESCRIPTION (provided by applicant): Cancer is a major health problem worldwide and new therapies are critically needed, especially for glioblastoma the most fatal brain tumor. Unpublished studies in our lab have revealed a new bystander effect for tumor suppressor p53. Upon activation by chemo- or radiation therapies p53 induces the death of adjacent tumor cells, while sparing normal cells. We discovered that the effecter mechanism relies upon the secretion of galectin-3, a �-galactose-recognizing lectin, which induces apoptosis. We also found that secreted galectin-3 reduced tumor formation in vivo. In this proposal we will extend these initial findings by dissecting the underlying mechanisms and determine whether Gal3 has clinical potential. We will determine the type of apoptotic signaling pathways activated in tumor cells by extracellular galectin-3 (Aim 1), whether secreted galectin-3 selectively binds to a specific cell surface receptor, with tumor-specific characteristics (Aim 2), and whether Gal-3 delivery can be used as a viable therapeutic for cancer using an in vivo mouse glioma model (Aim 3). Our working hypothesis is that p53 exerts a tumor suppressive bystander effect by stimulating exosomal secretion of Gal3, which in turn binds in a tumor-selective fashion to � 1-integrin complexes due to unique N-glycanation in cancer, and induces a therapeutic effect by activating apoptosis. These studies are important because we identified a new p53-induced tumor suppressive mechanism mediated by soluble Gal3, which has therapeutic implications. Examining the role of extracellular Gal3 in glioma apoptosis and tumor growth in vivo is novel. These studies will provide proof-of-principle data for targeting cancer with Gal3 (or agonists such as peptidomimetics or small molecules). Successful outcome of this project will support the clinical translation of Gal3 for the treatment of malignant glioma and possibly other cancers, which is highly relevant to public health.