Glioblastoma multiforme (GBM) is both the most common and lethal primary malignant brain tumor. In the last century we have accumulated tremendous amounts of data on this type of cancer, but we have achieved very little improvement in its treatment. Despite decades of concerted effort and advances in surgery, radiation and chemotherapy, the median survival is 15 months. The inadequate progress in treatment led us to reexamine the gliomagenesis theory and reconsider the cell of origin of this deadly disease. We recently developed a mouse glioma model using Cre-inducible lentiviral vectors that faithfully recapitulate the pathophysiology of human glioblastomas. Using this model, our results suggested that most differentiated cells in the central nervous system (CNS) upon defined genetic alterations undergo reprogramming to generate a neural stem cell (NSC) or progenitor state to initiate and maintain the tumor progression, as well as to give rise to the heterogeneous populations observed in malignant gliomas. We also reported the transdifferentiation of tumor cells to form tumor derived endothelial cells (TDEC) to generate new tumor blood vessels. I propose a multidisciplinary approach to investigate the mechanisms of tumor cell reprogramming and the potential development of novel therapeutic modalities. I will combine molecular biology, cancer biology, immunology, biochemistry and nanotechnology to address these lines of investigation both in vitro and in vivo in a novel mouse model of GBM.