Our laboratory is focused on understanding how invading brain tumor cells interact with the components of the tumor microenvironment, and how these key interactions influence glioma initiation, progression, and invasion. We use both in vivo and ex vivo model systems to study the interaction between tumor cells and the microenvironment including microglia, macrophages, reactive astrocytes, and the extracellular matrix. These studies are designed to identify novel determinants of gliomagenesis with potential for therapeutic targeting. In addition, using primary human brain tumors we are investigating potential diagnostic and prognostic brain tumor biomarkers.
Current Research Projects
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Heparan Sulfate Proteoglycans Regulate Oncogenic Signaling
Heparan sulfate proteoglycans (HSPGs), present on the cell surface and in the extracellular matrix, regulate the activity of multiple ligand-mediated cellular signaling pathways, including receptor tyrosine kinases (RTKs). In our studies, we have identified a novel mechanism by which glioblastoma (GBM), the most common and most malignant type of primary brain cancer, alters HSPGs to promote RTK signaling and drive tumor growth. We hypothesize that ligand availability in the tumor microenvironment is a critical determinant of oncogenic signaling in a subset of tumors and that identification of this subset is important for therapy. To test this hypothesis we are studying how HSPG alterations change tumor cell behaviors, including proliferation, invasion, and recruitment of inflammatory cells. While therapeutic targeting of single kinases has been largely disappointing in GBM, a drug targeting HSPGs has the potential to simultaneously 1) inhibit multiple oncogenic pathways in tumor cells and 2) disrupt critical tumor-microenvironment interactions.
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Role of the Innate Immune Response in Brain Tumor Development and Invasion.
The innate immune response, particularly the macrophage response, is known to play an important role in disease for many peripheral cancers. While microglia/macrophages are abundant in human glial tumors their function in disease is largely unknown. Using human tumor samples, we have demonstrated that GBM subtypes differ with respect to both the number of microglia/macrophages and the expression of immune response genes, including microglia/macrophage signature genes. To identify the function of glioma-infiltrating microglia/macrophages we are taking three approaches: 1) Compare the inflammatory infiltrate in human brain tumors from different anatomical sites and from different tumor types, including infiltrative and non-infiltrative tumors, by flow cytometry and expression profiling in; 2) determine the function of microglia/macrophages in murine malignant astrocytomas using genetic and chemical methods to alter their behavior; and 3) directly visualize how microglia/macrophages influence tumor cell behaviors in vivo and ex vivo in brain tumor slice cultures.
In preliminary studies, we have shown that while the expression of immune response genes is enriched in patients with the shortest survival in adult GBM this is not true in the pediatric setting. These studies argue for important functional differences in the immune response between tumor subtypes and between adult and pediatric tumors. Understanding the potential differences between the function of the innate immune response in adult and pediatric brain tumors is of critical importance for both therapeutic stratification and for understanding disease biology.
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Modeling Human Brain Tumors
In addition to the hypothesis-driven projects above, we are also continuing to build tools to help us model human disease and measure changes in tumor biologic behavior. Currently, we use primary cultured human brain tumors, human brain tumor xenografts, and a robust murine model for astrocytoma that we adapted, based on the genetic manipulation of adult neural progenitor cells and orthotopic transplantation into immunocompetent mice. Using these models we can readily manipulate both the tumor cells and the tumor microenvironment independently. In addition, we are developing systems to quantify the dynamic cellular interactions in the tumor microenvironment in vivo and ex vivo using a spinning disk confocal microscope and fluorescently tagged tumor cells.