The primary focus of the NCI-funded MIT/DFCI Cancer Systems Biology Consortium U54 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 immunosuppressive 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. Data from the Center highlight the complex interactions of GBM tumor cells with their microenvironment, including altered transcriptional networks, metabolic utilization, and altered signaling in the tumor cells, macrophages and neurons during tumor evolution. Emerging data highlight selected pathways in disseminated tumor cells that may be responsible for enabling tumor cell invasion into the surrounding brain tissue and survival of these invasive cells. Results from the Center have also highlighted cell-surface peptide antigen targets on GBM tumor cells and glioma-associated macrophages and dendritic cells. Efforts are underway to develop targeted immunotherapies recognizing these peptide antigens.
Projects within the Center are highly multidisciplinary, involving researchers in the Department of Biological Engineering and Department of Biology in the MIT Koch Institute for Integrative Cancer Research; the Departments of Data Science and Statistics at the Dana-Farber Cancer Institute; the Departments of Neurosurgery and Radiology at Mass General Brigham; the Department of Radiation Oncology at the Mayo Clinic, and the Department of Neurological Surgery at the University of Miami. This team brings expertise in immunology, patient derived and murine models of GBM, computational modeling and computational biology, spatial metabolomics, spatial transcriptomics, and spatial proteomics, single cell transcriptomics, proteomics, phosphoproteomics, and immunopeptidomics, and integrative systems analysis; together these approaches provide unprecedented insight into the interactions and evolution of GBM tumor cells and their microenvironment.