Although monoclonal in origin, most tumors appear to contain heterogeneous populations of cancer cells. One possible explanation of this tumor heterogeneity is that human tumors are not merely monoclonal expansions of a single transformed cell, but rather caricatures of normal tissues, and their growth is sustained by cancer stem cells (CSCs). This conceptual shift has important implications, not only for understanding tumor biology but also for developing and evaluating effective anticancer therapies. These CSCs are thought to be more resistant to apoptosis, to survive therapy and to eventually give rise to second-line tumors, which are harder to eliminate by the first-line therapy. In this proposal, we are introducing our data in detection of CSCs in malignant peripheral nerve sheath tumors (MPNSTs) for the first time, and explain our plans for targeting these cells with a novel oncolytic virus developed in our lab. We have identified a sub-population of cells in primary human MPNST cells which are positive for CD133 (a well-known marker for CSCs) and other stem cell markers. The SS2 virus developed in our lab is capable of targeting CD133+ cells and we intend to investigate the effects of this virus as a novel therapeutic tool against MPNST. Oncolytic viruses are a novel of anti-cancer agents in advanced clinical trials which have obtained FDA approval for treatment of melanoma. We now intend to test the virus developed in our lab in the therapy of MPNST.