Joanna Phillips, MD, PhD

Assistant Professor
Department of Neurological Surgery
+1 415 514-4929

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.

Primary Thematic Area: 
Cancer Biology & Cell Signaling
Secondary Thematic Area: 
Neurobiology
Research Summary: 
Tumor-microenvironment interactions regulating brain tumorigenesis

Websites

Publications: 

Clonal expansion and epigenetic reprogramming following deletion or amplification of mutant IDH1.

Proceedings of the National Academy of Sciences of the United States of America

Mazor T, Chesnelong C, Pankov A, Jalbert LE, Hong C, Hayes J, Smirnov IV, Marshall R, Souza CF, Shen Y, Viswanath P, Noushmehr H, Ronen SM, Jones SJM, Marra MA, Cairncross JG, Perry A, Nelson SJ, Chang SM, Bollen AW, Molinaro AM, Bengtsson H, Olshen AB, Weiss S, Phillips JJ, Luchman HA, Costello JF

Heparan Sulfate Glycosaminoglycans in Glioblastoma Promote Tumor Invasion.

Molecular cancer research : MCR

Tran VM, Wade A, McKinney A, Chen K, Lindberg OR, Engler JR, Persson AI, Phillips JJ

Metabolic Profiling of IDH Mutation and Malignant Progression in Infiltrating Glioma.

Scientific reports

Jalbert LE, Elkhaled A, Phillips JJ, Neill E, Williams A, Crane JC, Olson MP, Molinaro AM, Berger MS, Kurhanewicz J, Ronen SM, Chang SM, Nelson SJ

A Kinase Inhibitor Targeted to mTORC1 Drives Regression in Glioblastoma.

Cancer cell

Fan Q, Aksoy O, Wong RA, Ilkhanizadeh S, Novotny CJ, Gustafson WC, Truong AY, Cayanan G, Simonds EF, Haas-Kogan D, Phillips JJ, Nicolaides T, Okaniwa M, Shokat KM, Weiss WA

Chemotherapy for adult low-grade gliomas: clinical outcomes by molecular subtype in a phase II study of adjuvant temozolomide.

Neuro-oncology

Wahl M, Phillips JJ, Molinaro AM, Lin Y, Perry A, Haas-Kogan DA, Costello JF, Dayal M, Butowski N, Clarke JL, Prados M, Nelson S, Berger MS, Chang SM