ABSTRACT – OVERALL The primary focus of the MIT/DFCI Center for Systems Biology of Glioblastoma is to understand the intersections between neurons, immune cells, and tumor cells in this deadly tumor. The lack of response to immunotherapy strategies despite prominent infiltrates of immune cells in many GBM highlights the immuno- suppressive nature of the GBM microenvironment and the importance of more clearly understanding the dynamic interactions at the tumor/immune interface. Similarly, interactions between tumor cells and neural cells in the tumor microenvironment have emerged as driving forces in tumor progression and invasion, with electrical signals from neurons providing growth and migration stimuli to tumor cells, while tumor cells lead to aberrant electrical signaling in local neurons. The central hypothesis of this proposal is that developing a systems-level understanding of the dynamic interactions between tumor cells, neurons and immune cells will provide unprecedented insights into glioma tumor biology and foster development of novel therapeutic strategies to abrogate tumor invasion, enhance the efficacy of cytotoxic therapies, and increase clearance of tumor burden by the innate and adaptive immune system. The planned analyses will enable building an integrated computational model of tumor-neural-immune interactions for GBM tumors. The model will be based on a foundation of in vitro, in vivo, and ex vivo model systems, and then validated in dozens of human patients. Image-registered biopsies from different tumor regions within each patient will be analyzed to test predictions of this model against the ‘ground truth’ of human tumors. The ultimate goal of the MIT/DFCI Center for Systems Biology of Glioblastoma is to improve patient care by using systems biology and computational modeling to identify therapeutic strategies to specifically disrupt critical tumor cell – microenvironment interactions.