Daniel J Brat, MD, PhD

Cancer Biology
Neuropathology

Professor
Pathology & Laboratory Medicine

Other Appointments/Positions

Vice Chair, Translational Programs, Department of Pathology and Laboratory Medicine

Director, Research Pathology Core Laboratory, Winship Cancer Insitute

Medical Director, Human Tissue Procurement Service, Winship Cancer Institute

Co-Director, Pathology Residency Training Program, Emory University School of Medicine

Director, Neuropathology Division, Emory University School of Medicine

Director, Neuropathology Fellowship, Emory University School of Medicine

Neuropathology Attending, Emory Healthcare Hospitals

Neuropathology Attending, Children's Healthcare of Atlanta Hospitals

Pathology Division(s):
Anatomic Pathology
Experimental Pathology

Email Address:
dbrat@emory.edu

Education:

MD   Mayo Medical School, Rochester MN, 1987 - 1994

PhD   Mayo Graduate School, Rochester MN, 1987 - 1994

Residency   Anatomic Pathology, Johns Hopkins Hospital, Baltimore, MD, 1994 - 1997

Fellowship   Neuropathology, Johns Hopkins Hospital, Baltimore, MD, 1997 - 1999

Research Interests:

- Mechanisms Underlying Glioblastoma Progression
We investigate mechanisms responsible for the biologic progression to glioblastoma (GBM), the highest grade astrocytoma, including genetic alterations, hypoxia, and angiogenesis. Progression to GBM is characterized pathologically by focal tumor necrosis, typically with surrounding pseudopalisading cells, and microvascular hyperplasia, a type of angiogenesis. We recently demonstrated that pseudopalisading cells around necrosis represent hypoxic tumor cells migrating away from central vascular occlusion, which is often associated with intravascular thrombosis. This process results in peripheral hypoxia-induced microvascular hyperplasia and neoplastic expansion outward. Since the pro-thrombotic protein tissue factor is known to be upregulated in gliomas, we are investigating whether genetic alterations or hypoxia may cause increased levels of its expression.

- Regulators of Asymmetric Cellular Division in Glioblastoma Stem Cells
We study mechanisms that confer specialized biologic properties to glioma stem cells (GSC) in GBM. The Drosophila brain tumor (brat) gene normally regulates asymmetric cellular division and neural progenitor differentiation in the CNS of flies and, when mutated, leads to a massive brain containing only neuroblastic cells with tumor-like properties. We study the human homolog of Drosophila brat, Trim3, for its role in regulating asymmetric cellular division and stem cell properties in GBMs.

Clinical Focus:

I am a diagnostic neuropathologist with a clinical and scientific interest in brain tumors. I am responsible, along with my two colleagues in neuropathology, for the pathlogic diagnosis of brain lesions from patients seen at Emory Healthcare Hospitals and Children's Healthcare of Atlanta Hospitals. I also direct the Neuropathology Fellowship and co-direct the Pathology residency, with an emphasis on recruitment and career development.

Honors / Awards:

Scientific Advisory Board, Southeastern Brain Tumor Foundation, 2009-

Glioblastoma Working Group, The Cancer Genome Atlas (TCGA) Project, National Cancer Institute (NCI), 2008-

Scientific Advisory Committee, Goldhirsh Foundation, 2008-

Neuropathology Committee, College of American Pathologists, 2006-present

Advisory Committee, World Health Organization Classification of Brain Tumors, 2006

Lucien J. Rubinstein Award, American Association of Neuropathologists, 2004

Pathology Committee, Radiation Therapy Oncology Group., 2000-present

Editorial Boards: Neuro-oncology; Journal of Neuropathology and Experimental Neurology; Brain Pathology; Archives of Pathology and Laboratory Medicine, Advances in Anatomic Pathology, American Journal of Clinical Pathology., 2000-present

Benjamin Castleman Award, United States and Canadian Academy of Pathology, 2000

Matthew T. Moore Award, American Association of Neuropathologists, 1997

Outstanding Research Publication Award, Armed Forces Institute of Pathology Symposium, 1997

Alpha Omega Alpha, 1996

Phi Beta Kappa, 1987

Specialty Boards:

1997 Diplomate, Anatomic Pathology, American Board of Pathology

1999 Diplomate, Neuropathology, American Board of Pathology

Selected Publications:

Published and Accepted Research Articles -

Rong Y, Belozerov V, Chen G, Tucker-Burden C, Durden DL, Van Meir EG, Mackman N, Brat DJ. (2009) EGFR and PTEN modulate tissue factor expression in glioblastoma through JunD/AP-1 transcriptional activity. Cancer Res 69:2450-49.

The Cancer Genome Atlas Network. (2008) Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature 455:1061-1068.

Brat DJ, Parisi JE, Kleinschmidt-DeMasters BK, Yachnis AT, Montine TJ, Boyer PJ, Suzanne Z.-E. Powell SZE, Prayson RA, McLendon RE. (2008) Surgical Neuropathology Update: A Review of Changes Introduced by the World Health Organization (WHO) Classification of Tumors of the Central Nervous System, 4th Edition. Arch Pathol Lab Med 132:993-1007.

Brat DJ, Prayson RA, Ryken TC, Olson JJ. (2008) Diagnosis of malignant glioma: role of neuropathology. J. Neuro-onc. 89:287-311

Tehrani M, Friedman TM, Olson JJ, Brat DJ. (2008) Intravascular thrombosis in central nervous system malignancies: A potential role in astrocytoma progression to glioblastoma. Brain Pathol 18:164-171.

Tang X, Jang SW, Wang X, Liu Z, Bahr SM, Sun SY, Brat DJ, Gutmann DH, Ye K. (2007) Akt phosphorylation regulates the tumour-suppressor merlin through ubiquitination and degradation. Nat. Cell Biol 9:1199-207.

Brat DJ, Shehata BM. Castellano-Sanchez AA, Hawkins C, Yost RB, Greco C, Mazewski, C, Janss A, Ohgaki H, Perry A. (2007) Congenital glioblastoma: a clinico-pathologic and genetic analysis. Brain Pathol.17: 276-81.

Brat DJ, Scheithauer BW, Fuller G, Tihan T. (2007) Newly codified glial neoplasms in the WHO classification of tumours of the central nervous system 2007: angiocentric glioma, pilomyxoid astrocytoma and pituicytoma. Brain Pathol. 17:319-24.

Rong Y, Durden DL, Van Meir EG, Brat DJ (2006). "Pseudopalisading" necrosis in glioblastoma: a familiar morphologic finding that links vascular pathology, hypoxia, and angiogenesis. J. Neuropathol. Exp. Neurol. 65:529-39.

Khwaja FW, Nolen JDL, Mendrinos S, Lewis MM, Olson, JJ, Van Meir EG, Ritchie JC, Brat DJ. (2006). Proteomic analysis of cerebrospinal fluid discriminates malignant and non-malignant CNS disease and identifies specific protein markers. Proteomics 6:6277-87.

Rong Y, Hu F, Huang RP, Mackman N, Horowitz JM, Jensen RL, Durden DL, Van Meir EG, Brat DJ. (2006) Egr-1 regulates hypoxia-induced expression of tissue factor in glioblastoma through HIF-1¿ independent mechanisms. Cancer Res 66: 7067-74.71.

Gupta M, Djalilvand A, Brat DJ. (2005) Clarifying the diffuse gliomas: an update on morphology and markers that discriminate oligodendroglioma from astrocytoma. Am. J Clin Pathol 124:1-14.

Brat DJ, Bellail AC, Van Meir EG. (2005) The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesis. Neuro-oncol. 7:122-133.

Pieper AA, Wu X, Han TW, Estill SJ, Wu L, Dang Q, Reece-Fincanon S, Dudley CA, Richardson J, Brat DJ, McKnight SL. (2005) The neuronal PAS domain protein 3 transcription factor controls FGF-mediated adult hippocampal neurogenesis in mice. Proc. Natl. Acad. Sci. U.S.A. 102:14052-7.

Rong Y, Post DE, Pieper RO, Durden DL, Van Meir EG, Brat DJ (2005) PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastoma. Cancer Res. 65:1406-13.

Brat DJ, Van Meir EG. (2004) Vaso-occlusive and pro-thrombotic mechanisms of tumor hypoxia, necrosis, and accelerated growth in glioblastoma. Lab Invest 84:397-405.

Junge CE, Lee CJ, Hubbard KB, Zhang Z, Olson, JJ, Hepler JR, Brat DJ Traynelis SF (2004). Protease activated receptor-1 (PAR1) in human brain: localization and functional expression in astrocytes. Exp. Neurol. 188:94-103.

Brat, DJ, Seiferheld W, Perry A, Hammond E, Murray KJ, Schulsinger A, Mehta M, Curran W (2004). Analysis of 1p, 19q, 9p, and 10q as prognostic markers for high grade astrocytomas using fluorescence in situ hybridization on tissue micro-arrays from RTOG trials. Neuro-oncology 6:96-103.

Cushing MM, Brat DJ, Mosunjac MI, Guasch A, Hennigar RA, Jernigan D, Petersen L, Goldsmith C, Rollin PE, Shieh WJ, Guarner J, Zaki SR (2004). Fatal West Nile virus infection in renal transplant recipient. Am. J. Clin. Pathol. 121:26-31.

Castellano-Sanchez AA, Li S, Qian J, Lagoo A, Weir E, Brat DJ. (2004) Central nervous system post-transplant lymphoproliferative disorders. Am. J. Clin. Pathol. 121:246-253.

Brat DJ, Castellano-Sanchez A, Hunter SB, Pecot MJ, Cohen C, Hammond EH, Kaur B, Van Meir EG (2004). Pseudopalisading cells in glioblastoma are hypoxic, express extracellular matrix proteases, and are formed by a rapidly migrating population. Cancer Res. 64:920-7.

Brat DJ, Mapstone TB. (2003) Malignant glioma physiology: cellular response to hypoxia and its role in tumor progression. Ann Intern Med 138:659-668.

Junge CE, Sugawara T, Mannaioni G, Alagarsamy S, Conn PJ, Brat DJ, Chan P, Traynelis SF (2003). The contribution of protease activated receptor-1 to neuronal damage caused by transient focal ischemia. Proc. Natl. Acad. Sci. U.S.A 100:13019-24.

Castellano-Sanchez AA, Ohgaki H, Yokoo H, Scheithauer BW, Burger PC, Hamilton RL Finkelstein SD, Brat DJ. (2003) Granular cell astrocytomas show a high frequency of allelic loss but are not a genetically defined subset. Brain Pathol 13:185-194.

Brat DJ, Castellano-Sanchez A, Kaur B, Van Meir EG. (2002) Genetic and biologic progression in astrocytomas and their relation to angiogenic dysregulation. Adv. Anat. Pathol. 9:24-36.

Brat DJ, Scheithauer BW, Medina-Florez R, Rosenblum MK, Burger PC. (2002) Infiltrative astrocytomas with granular cell features (granular cell astrocytomas): a study of morphology, grading, and outcome. Am J Surg Pathol 26:750-757.

Brat DJ, Van Meir EG. (2001) Glomeruloid microvascular proliferation orchestrated by VPF/VEGF: a new world of angiogenesis research. Am. J. Pathol. 158: 789-796.

Brat DJ, Scheithauer BW, Eberhart CG, Burger PC. (2001) Extra-ventricular neurocytomas: pathologic features and clinical outcome. Am. J. Surg. Pathol. 25:1252-1260.

Baisden BL, Brat DJ, Melhem ER, Rosenblum MK, King P, Lantos PL, Burger PC. (2001) Dysembryoplastic neuroepithelial tumor of the septum pellucidum: a lesion often misdiagnosed as a glioma. Report of ten cases. Am. J. Surg. Pathol. 25:494-499.

Brat DJ, Scheithauer BW, Staugaitis SM, Holtzman RN, Morgello S, Burger PC. (2000) Pituicytoma: a distinctive low grade glioma of the neurohypophysis. Am. J. Surg. Pathol. 24:362-368.

Brat, D.J., Hirose, Y., Cohen, K.J., Feuerstein, B.G., Burger, P.C. (2000) Astroblastoma: clinicopathologic features and chromosomal abnormalities defined by comparative genomic hybridization. Brain Pathol. 10:342-352.

Brat DJ, James CD, Jedlicka AE, Connolly DC, Chang E, Castellani RJ, Schmid M, Schiller, M, Carson DA, Burger PC. (1999). Molecular genetic alterations in radiation-induced astrocytomas. Am. J. Pathol. 154:1431-1438.

Brat DJ, Giannini C, Scheithauer BW, Burger PC. (1999). Primary melanocytic neoplasms of the central nervous system. Am. J. Surg. Pathol. 23: 745-754.

Pieper AA, Brat DJ, Krug DK, Watkins CC, Gupta A, Blackshaw S, Verma A, Wang Z-Q, Snyder SH. (1999). Poly (adp-ribose) polymerase deficient mice are protected from streptozotocin-induced diabetes. Proc. Natl. Acad. Sci. U.S.A. 96:3059-3064.

Brat DJ, Scheithauer BW, Staugaitis SM, Cortez SC, Brecher K, Burger PC. (1998). Third ventricular "chordoid glioma": a distinct clinicopathologic entity. J. Neuropathol. Exp. Neurol. 57:283-290.

Book Chapters -

Louis DN, Reifenberger G, Brat DJ, Ellison DW. (2008) Tumours: Introduction and Neuroepithelial Tumours. In Love, S, Louis, DN and Ellison, D, eds. Greenfield's Neuropathology, 8th Edition, London: Hodder Arnold.

Wesseling P, Brat DJ, Fuller GN. (2007) Pituicytoma. In Louis DN, Ohgaki H, Weistler OD, and Cavenee WK, eds WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon: Intl. Agency for Research.

Brat DJ, VandenBerg SR, Figarella-Branger D, Taratuto AL. (2007) Desmoplastic infantile astrocytoma and ganglioglioma. In Louis DN, Ohgaki H, Weistler OD, and Cavenee WK, eds WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon: Intl. Agency for Research.

Brat DJ, Perry A. (2007) Melanocytic lesions. In Louis DN, Ohgaki H, Weistler OD, and Cavenee WK, eds WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon: Intl. Agency for Research.

Kleihues P, Burger PC, Aldape K, Brat DJ, Biernat W, Bigner, DD, Nakazato Y, Plate KH , Giangaspero F, vonDeimling A, Ohgaki H, Cavenee WK. (2007) Glioblastoma. In Louis DN, Ohgaki H, Weistler OD, and Cavenee WK, eds. WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon: Intl. Agency for Research.

Brat DJ, Scheithauer BW. (2007) Chordoid glioma of the third ventricle. In Louis DN, Ohgaki H, Weistler OD, and Cavenee WK, eds. WHO Classification of Tumours of the Central Nervous System. 4th ed. Lyon: Intl. Agency for Research.

Brat DJ (2006) Meningeal Melanocytoma, Neurocutaneous Melanosis, and Primary Meningeal Melanoma. In McLendon, RE, Bigner, DD, Rosenblum M and Bruner JM, eds. Russell and Rubinstein's Pathology of Tumors of the Nervous System, 7th Edition. London: Edward Arnold.

Brat DJ (2006) Chordoid Glioma of the Third Ventricle. In McLendon, RE, Bigner, DD, Rosenblum M and Bruner JM, eds. Russell and Rubinstein's Pathology of Tumors of the Nervous System, 7th Edition. London: Edward Arnold.

Brat DJ (2005) Overview of Anatomy and Histology of the Central Nervous System. In Prayson RA, ed. Foundations in Diagnostic Pathology, Neuropathology. Philadelphia: Churchill Livingstone.

Van Meir EG, Hao C, Post DE, Liau LM, Brat DJ (2003) Development of molecular therapy for specific targeting of pathways that permit brain tumor development. In Zhang W and Fuller GN (eds.) Genomic and Molecular Neuro-Oncology. Sudbury, MA: Jones and Bartlett Publishers Inc.