Joanna Phillips, MD, PhD

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

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: 

Heparan sulfate synthesized by Ext1 regulates receptor tyrosine kinase signaling and promotes resistance to EGFR inhibitors in GBM.

Molecular cancer research : MCR

Ohkawa Y, Wade A, Lindberg OR, Chen KY, Tran VM, Brown SJ, Kumar A, Kalita M, James CD, Phillips JJ

Comprehensive analysis of diverse low-grade neuroepithelial tumors with FGFR1 alterations reveals a distinct molecular signature of rosette-forming glioneuronal tumor.

Acta neuropathologica communications

Lucas CG, Gupta R, Doo P, Lee JC, Cadwell CR, Ramani B, Hofmann JW, Sloan EA, Kleinschmidt-DeMasters BK, Lee HS, Wood MD, Grafe M, Born D, Vogel H, Salamat S, Puccetti D, Scharnhorst D, Samuel D, Cooney T, Cham E, Jin LW, Khatib Z, Maher O, Chamyan G, Brathwaite C, Bannykh S, Mueller S, Kline CN, Banerjee A, Reddy A, Taylor JW, Clarke JL, Oberheim Bush NA, Butowski N, Gupta N, Auguste KI, Sun PP, Roland JL, Raffel C, Aghi MK, Theodosopoulos P, Chang E, Hervey-Jumper S, Phillips JJ, Pekmezci M, Bollen AW, Tihan T, Chang S, Berger MS, Perry A, Solomon DA

Patient-derived cells from recurrent tumors that model the evolution of IDH-mutant glioma.

Neuro-oncology advances

Jones LE, Hilz S, Grimmer MR, Mazor T, Najac C, Mukherjee J, McKinney A, Chow T, Pieper RO, Ronen SM, Chang SM, Phillips JJ, Costello JF

Recurrent tumor and treatment-induced effects have different MR signatures in contrast enhancing and non-enhancing lesions of high-grade gliomas.

Neuro-oncology

Cluceru J, Nelson SJ, Wen Q, Phillips JJ, Shai A, Molinaro AM, Alcaide-Leon P, Olson MP, Nair D, LaFontaine M, Chunduru P, Villanueva-Meyer JE, Cha S, Chang SM, Berger MS, Lupo JM

Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition.

Acta neuropathologica

Mondal G, Lee JC, Ravindranathan A, Villanueva-Meyer JE, Tran QT, Allen SJ, Barreto J, Gupta R, Doo P, Van Ziffle J, Onodera C, Devine P, Grenert JP, Samuel D, Li R, Metrock LK, Jin LW, Antony R, Alashari M, Cheshier S, Whipple NS, Bruggers C, Raffel C, Gupta N, Kline CN, Reddy A, Banerjee A, Hall MD, Mehta MP, Khatib Z, Maher OM, Brathwaite C, Pekmezci M, Phillips JJ, Bollen AW, Tihan T, Lucas JT, Broniscer A, Berger MS, Perry A, Orr BA, Solomon DA