Daniel J Brat, MD,PhD

Information

Name

Daniel J Brat, MD,PhD

Title

Magerstadt Professor and Chair of Pathology

Email

daniel.brat@northwestern.edu

Office Phone

404-503-8144

Department

Pathology

Office

Ward 3-140

Areas of Research

Cell Biology, Imaging & Microscopy, Molecular Neuroscience

Current Research

Current Research

The Brat Lab investigates the biological underpinnings of glioma biology and is focused primarily on those mechanisms that lead to the most aggressive form of glioma, glioblastoma (GBM). We study genetics, hypoxia, stem cells and angiogenesis and use patient-derived samples as well as mouse and Drosophila models. Rapid growth of human gliomas is characterized by tumor necrosis, severe hypoxia and microvascular hyperplasia, a type of angiogenesis. We proposed that vaso-occlusion and intravascular thrombosis within a high grade glioma results in hypoxia, necrosis and hypoxia-induced microvascular hyperplasia in the tumor’s periphery, leading to neoplastic expansion outward. We are determining if transcriptional profiles, signaling networks and therapeutic targets vary within this altered micro-environment, and have also begun investigations involving the enrichment of glioma stem cells and influx of tumor associated macrophages. We use in vivo, multipohoton microscopy to monitor glioma dynamics following the onset of necrosis in a mouse model.

We also study mechanisms that confer specialized biologic properties to glioma stem cells (GSC) in GBM, including their ability to divide asymmetrically and their ability to home to hypoxic micro-environments. 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 cell division and stem-like properties in GSCs. We are currently investigating those gene products that antagonize the tumor promoting effects of Brat/Trim3 loss on brain tumor development and are focused on CDK5/p35. For these studies, we use Drosphila as the primary model for discovery and translate findings to mouse xenograft models using patient-derived, genetically characterized gliomas.

Selected Publications

Selected Publications

Chen G, Kong J, Tucker-Burden C, Anand M, Rong Y, Rahman F, Moreno CS, Van Meir EG, Hadjipanayis CG, Brat DJ. (2014) Human Brat ortholog TRIM3 is a tumor suppressor that regulates asymmetric cell division in glioblastoma. Cancer Res. 74:4536-48.

Zerrouqi A, Pyrzynska B, Brat DJ, Van Meir EG. (2014) p14ARF suppresses tumor-induced thrombosis by regulating the tissue factor pathway. Cancer Res 74:1371-8.

The Cancer Genome Research Network (2015). Comprehensive and Integrative Genomic Characterization of Diffuse Lower Grade Gliomas. N Eng J Med 372:2481-98. *Corresponding Author

Chen K, Yang D, Li X, Sun B, Song F, Cao W, Brat D, Gao Z, Li H, Liang H,Zhao Y, Zheng H, Li M, Buckner J, Patterson SD, Ye X, Reinhard C, Bhathena A, Joshi D, Mischel PS, Croce C, Wang YM, Kaimal S, Li H, Lu X, Pan Y, Chang H, Ba S, Luo L, Cavenee W, Zhang W, Xishan Hao X. (2015) Mutational landscape of gastric adenocarcinoma in Chinese: implications for prognosis and therapy. Proc Natl Acad Sci. 112:1107-12.

Lin R, Elf S, Shan C, Kang H-B, Ji Q, Zhou L, Hitosugi T, Zhang L, Zhang S, Seo JH, Xie J, Tucker M, Gu T-L, Sudderth J, Jiang L, Mitsche M, DeBerardinis RJ, Wu S, Li Y, Mao H, Chen PR, Wang D, Chen GZ, Hurwitz SJ, Lonial S, Arellano ML, Khoury HJ, Khuri FR, Lee BH, Brat DJ, Ye K, Boggon TJ, He C, Kang S, Fan J, Chen J (2015) 6-phosphogluconate dehydrogenase links oxidative PPP, lipogenesis and tumor growth by inhibiting LKB1-AMPK signaling. Nat Cell Biol. 17:1484-96.

Zhang S, Chan C-B, Zhou W, Chen J, Lu, H, Appin C, Brat DJ, Ye K. (2016) Fyn-phosphorylated PIKE-A binds and inhibits AMPK signaling, blocking its tumor suppressive activity. Cell Death Differ 23:52-63.

Ceccarelli M, Barthel FP, Malta TM, Sabedot TS, Pagnotta SM, Murray BA, Radenbaugh A, Morozova O, Newton Y, Anjum S,, Wang J, Manyam G, Brat DJ, Zoppoli P, Akbani R, Ling S, Cherniack AD, Zhang H, Poisson L, Rao A, Mikkelsen T, Yung WKA, Huse J, Rao G, Lau CC, Rao A, Grifford M, Wrensch M, Beroukhim R, Cooper L, Rabadan R, Aldape KD, Laird PW, Gutmann DH, Salama SR, Noushmehr H, Iavarone A, Verhaak RGW, TCGA Research Network (2016) Integrated characterization of genomic, epigenomic and transcriptomic activities reveals novel relationships between histological subtypes and molecular signatures in diffuse low- and high-grade glioma. Cell 164:550-63.

Hinrichs BH, Newman S, Appin CL , Dunn W, Cooper L, Pauley R, Kowalski J, Rossi MR, Brat DJ (2016) Farewell to GBM-O: genomic and transcriptomic profiling of glioblastoma with oligodendroglioma component (GBM-O) reveals distinct molecular subgroups. Acta Neuropathol Comm 4:4
DOI: 10.1186/s40478-015-0270-7.

Mukherjee S, Tucker-Burden C, Zhang C, Moberg K, Read R, Costas G. Hadjipanayis CG, Brat, DJ. (2016) Drosophila Brat and human ortholog TRIM3 maintain stem cell equilibrium and suppress brain tumorigenesis by attenuating Notch nuclear transport. Cancer Res 76:2443-52.

Selagea L, Mishra A, Anand M, Ross J, Tucker-Burden C, Kong J, Brat DJ. (2016) EGFR and C/EBP-β oncogenic signaling is bidirectional in human glioma and varies with C/EBP-β isoform. FASEB J. 12:4098-4108.

Zhang C, Mukherjee S, Tucker-Burden C, Ross J, Chau MJ, Kong J, Brat DJ. (2017) Trim8 regulates stemness in glioblastoma through PIAS3-STAT3. Mol Oncol 11:280-294

Qi Q, Kang S-S, Zhang S, Pham C, Fu H, Brat DJ, Ye K (2017) Co-amplification of Phosphoinositide 3-kinase enhancer A and Cyclin-dependent kinase 4 triggers glioblastoma progression. Oncogene 36:4562-4572.

Patel SH, Poisson LM, Zhou Y, Cooper LAD, Brat DJ, Snuderl M, Thomas C, Franceschi AM, Griffith B, Golfinos JG, Chi A, Jain R. (2017) T2-FLAIR Mismatch, an Imaging Biomarker for IDH Status in Lower Grade Gliomas: A TCGA/TCIA Project. Clin Can Res 23:6078-6085.

Yousuf S, Brat D, Shu HK, Wang Y, Stein D, Atif F (2017) Progesterone improves neurocognitive outcomes following therapeutic cranial irradiation in mice. Horm Behav 96:21-30.

Liang Y, Wang F, Zhang P, Saltz JH, Brat DJ, Kong J. (2017) Development of a Framework for Large Scale Three-Dimensional Pathology and Biomarker Imaging and Spatial Analytics. AMIA Jt Summits Transl Sci Proc. 2017:75-84.

Yousefi S, Amrollahi F, Amgad M, Dong C, Lewis JE, Gutman DA, Halani S, Velazquez Vega JE, Brat DJ, Cooper LAD (2017) Predicting clinical outcomes from heterogeneous cancer genomic profiles with deep learning. Sci Rep 7(1):11707.

Nalisnik M, Amgad M, Lee S, Halani S, Velazquez Vega J, Brat DJ, Gutman DA, Cooper LAD (2017)
Interactive phenotyping of large-scale histology imaging data with HistomicsML. Sci Rep 7(1):1458.

Ross JL, Cooper LAD , Gutman D, Kong J, Williams M, Tucker-Burden C, McCrary MR, Bouras A, Kaluzova M, Dunn Jr. WD, Duong D, Hadjipanayis C, Brat DJ (2017) Differential expression of oncogenic proteins across tumor microenvironments and at infiltrative margins in glioblastoma. Sci Rep 7(1):15593.