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 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, 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 vivo in brain tumor slice cultures.
Wade A, Robinson AE, Engler JR, Petritsch C, David James C, Phillips JJ. Proteoglycans and their roles in brain cancer. FEBS J. 2013 Jan 2.
Phillips JJ, Aranda D, Ellison DW, Judkins AR, Croul SE, Brat DJ, Ligon KL, Horbinski C, Venneti S, Zadeh G, Santi M, Zhou S, Appin CL, Sioletic S, Sullivan LM, Martinez-Lage M, Robinson AE, Yong WH, Cloughesy T, Lai A, Phillips HS, Marshall R, Mueller S, Haas-Kogan DA, Molinaro AM, Perry A. PDGFRA amplification is common in pediatric and adult high-grade astrocytomas and identifies a poor prognostic group in IDH1 mutant glioblastoma. Brain Pathol. 2013 Feb 25.
Huillard E, Hashizume R, Phillips JJ, Griveau A, Ihrie RA, Aoki Y, Nicolaides T, Perry A, Waldman T, McMahon M, Weiss WA, Petritsch C, James CD, Rowitch DH. Cooperative interactions of BRAFV600E kinase and CDKN2A locus deficiency in pediatric malignant astrocytoma as a basis for rational therapy. Proc Natl Acad Sci U S A. 2012 May 14.
Engler JR, Robinson AE, Smirnov I, Hodgson JG, Berger MS, Gupta N, James CD, Molinaro A, Phillips JJ. Increased microglia/macrophage gene expression in a subset of adult and pediatric astrocytomas. PLoS One. 2012; 7(8).
Elkhaled A, Jalbert LE, Phillips JJ, Yoshihara HA, Parvataneni R, Srinivasan R, Bourne G, Berger MS, Chang SM, Cha S, Nelson SJ. Magnetic Resonance of 2-Hydroxyglutarate in IDH1-Mutated Low-Grade Gliomas. Sci Transl Med. 2012 Jan 11; 4(116).
Lu KV, Chang JP, Parachoniak CA, Pandika MM, Aghi MK, Meyronet D, Isachenko N, Fouse SD, Phillips JJ, Cheresh DA, Park M, Bergers G. VEGF Inhibits Tumor Cell Invasion and Mesenchymal Transition through a MET/VEGFR2 Complex. Cancer Cell. 2012 Jul 10; 22(1):21-35.
Phillips JJ. Novel therapeutic targets in the brain tumor microenvironment. Oncotarget. 2012; 3(5):568-75.
Phillips JJ, Huillard E, Robinson AE, Ward A, Lum DH, Polley MY, Rosen SD, Rowitch DH, Werb Z. Heparan sulfate sulfatase SULF2 regulates PDGFRa signaling and growth in human and mouse malignant glioma. J Clin Invest. 2012 Mar 1; 122(3):911-22.