Joanna Phillips, MD, PhD

In our laboratory we are interested in determining how interactions in the brain tumor microenvironment help drive tumorigenesis and invasion. Glioblastoma (GBM), a highly malignant brain tumor of adults and children, is characterized by diffuse invasion and abnormal activation of receptor tyrosine kinase signaling pathways. Despite many advances in our understanding of the biology of these tumors their treatment remains challenging. In the laboratory, we use both in vivoand 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, we are investigating proteoglycans and their glycosaminoglycan (GAG) side chains as potential diagnostic and prognostic brain tumor biomarkers.

Proteoglycans regulate oncogenic signaling in brain tumors.  In the brain, extracellular proteoglycans play critical roles in the regulation of cell signaling, migration, and differentiation via their interactions with extracellular ligands, growth factor receptors, extracellular matrix components, and intracellular proteins. In addition, proteoglycans help regulate the inflammatory response. Heparan sulfate and chondroitin sulfate proteoglycans (HSPGs and CSPGs) are abundant in GBM, and in the laboratory we are studying the cellular and molecular mechanisms by which alterations in proteoglycan core protein expression, GAG synthesis, and sulfation help drive brain tumorigenesis. As a part of these studies, we are also testing ways to therapeutically target proteoglycans and to use them as blood biomarkers of disease.

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 vivoin brain tumor slice cultures.