Glioblastoma (GBM) is an aggressive malignancy with a 5-year overall survival of less than 3%. Crosstalk between heterogeneous cell types within GBM tumors such as cancer stem cells (CSCs) and tumor-associated immune cells supports the development and progression of GBM. While many cell-intrinsic pathways that drive CSC maintenance in GBM have been identified, how the tumor microenvironment is altered in GBM to facilitate tumor cell growth is not well understood. Secreted proteins are a mechanism by which immune cells in the tumor microenvironment can foster tumor growth. My laboratory recently discovered that the metalloproteinase ADAMDEC1 is highly expressed in GBM compared to normal brain tissue and demonstrated expression and functional relevance of ADAMDEC1 in GBM CSCs. Additional studies by other groups suggest that ADAMDEC1 may be important in additional cell types within the GBM tumor microenvironment. Specifically, gene expression studies of microglia and brain-infiltrating myeloid cells isolated from multiple mouse GBM models and human GBM specimens found that ADAMDEC1 is one of the most highly upregulated genes compared to naive microglia and myeloid cells. These studies are intriguing given that ADAMDEC1 is not expressed in any cell type in the healthy brain, including microglia (although it is expressed at modest levels in bone marrow myeloid cells). ADAM family metalloproteinases are involved in cleaving/shedding proteins from the cell surface. I hypothesize that ADAMDEC1 cleaves and releases cytokines and growth factors from the surface of glioma-associated myeloid cells (GAMs), which has two major effects: activating growth-stimulatory pathways in GBM cells to drive CSC growth and self-renewal, and recruiting immunosuppressive immune cells to the tumor.
Aim 1 will test the hypothesis that ADAMDEC1 expression in GAMs promotes GBM progression through release of CSC-driving cytokines and growth factors from the cell surface of GAMs.
Aim 1 A will measure expression of Adamdec1 in GAMs compared to nave myeloid cells, Aim 1B will determine the effect of deleting Adamdec1 in GAMs on GBM growth, and Aim 1C will identify factors cleaved from the GAM cell surface by ADAMDEC1.
Aim 2 will test the hypothesis that ADAMDEC1 expression in GAMs promotes immune infiltration and an immunosuppressive tumor microenvironment.
Aim 2 A will measure the effects of Adamdec1 loss on the GBM-associated immune landscape.
Aim 2 B will perform rescue experiments to identify contributions of microglia-derived and bone marrow-derived Adamdec1 to the tumor immune landscape. The proposed research will provide me with a foundation in new areas including tumor-microenvironment interactions and neuroimmunology. Training in these topics will be crucial to realizing one of my long-term research goals of identifying ways to disrupt tumor-immune interactions for therapeutic benefit. Expertise in neurobiology, immunology, biochemistry, and clinical neuro- oncology from my mentors, lab members and collaborators at Cleveland Clinic will aid in successful completion of the proposed project.
Glioblastoma is a lethal brain tumor existing in a complex tumor microenvironment with multiple interconnected cell types. This proposal seeks to investigate how immune cells in the tumor microenvironment communicate with tumor cells and recruit additional immune cells to support tumor growth. Understanding these mechanisms can potentially open opportunities for novel clinical interventions.
