Michael Berens, Ph.D.

Professor
Clinical Genomics and Therapeutics Division

Head
Glioma Research Lab

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The Brain Tumor Unit at TGen studies cancers that originate in the brain and cancers that metastasize to the brain. Specific anatomic and physiologic aspects of the central nervous system establish unique interactions between tumor cells and host cells, which we pursue with the intent of opening new treatment approaches to this devastating disease. Three pillars of study dominate the landscape of the BTU’s research: Invasion Biology, Treatment Development, and Correlative Studies to Clinical Trials.

Invasion Biology

Cancer is fatal due to dissemination of the disease. This invasion disrupts the function of the adjacent tissue and organ, which in the case of primary brain tumors leads to devastating neurological deficits, and in the case of metastatic cancers to the brain leads to treatment challenges inherent to delivery across the blood brain barrier. We (and others) have observed an inverse relationship between cancer cell migration and proliferation. This led to a paradigm dubbed “go versus grow”, where proliferation (growth) is achieved at the expense of invasion (go). Cancer cells are not all the same. Some cancer cells disperse to expand the area of disease, while others are highly committed to numerical expansion in a restricted area. The functional property of “stemness” of cancer cells interdigitates in the invasion biology, as well do fluctuations in vulnerability to therapy associated with invasion.

In collaboration with an interdisciplinary team, we are studying the changes in glioma gene expression that accompany the transition of cell egress from multicellular spheroids and tumor, the adoption of an invasive/migratory phenotype, and the subsequent cessation of invasion that coincides with resumed proliferation. These experiments are designed to discover key genetic regulation of the cancer cell transition from proliferative to migratory behaviors. The findings may indicate strategies by which to control the spread and metastasis of cancer.

Treatment Development

The translational applications of our studies include the discovery and validation of markers of glioma invasion, which are explored for value as therapeutic targets. Preclinical validation of these targets fosters maturation of assays by which to test for inhibitors. The lab has developed and employed screening technologies by which to test libraries of small molecules for their migration-arresting properties. Active candidate compounds are being tested for synergistic effects with conventional chemotherapeutic agents or with radiation therapy. Preliminary preclinical in vivo experiments support the potentiation of cytotoxic therapy when tumors are treated with migration arresting compounds. Expression of epitopes on brain tumors suitable for immune targeting is an active and emerging pursuit.

Correlative Studies to Clinical Trials

Signals of tumor response or non-response (resistance or subclonal emergence) offer enormous value to the drug development enterprise. The Brain Tumor Lab develops pharmacokinetic assays indicative of “target-hit” and “efficacy”, which are tailored to targeted therapeutics as well as broadly instructive of early detection of treatment outcome, which accelerate and make-precise the use of new agents.

Publications

TNF-like weak inducer of apoptosis (TWEAK) promotes glioblastoma cell chemotaxis via Lyn activation. Dhruv HD, Whitsett TG, Jameson NM, Patel F, Winkles JA, Berens ME, Tran NL. Carcinogenesis. 2013 Aug 23. [Epub ahead of print]
Clinical trials in cellular immunotherapy for brain/CNS tumors. Badhiwala J, Decker WK, Berens ME, Bhardwaj RD. Expert Rev Neurother. 2013 Apr;13(4):405-24. doi: 10.1586/ern.13.23.
Reciprocal Activation of Transcription Factors Underlies the Dichotomy between Proliferation and Invasion of Glioma Cells. Dhruv HD, McDonough Winslow WS, Armstrong B, Tuncali S, Eschbacher J, Kislin K, Loftus JC, Tran NL, Berens ME. PLoS One. 2013;8(8):e72134. doi: 10.1371/journal.pone.0072134.
RTK inhibition: looking for the right pathways toward a miracle. Xie Q, Vande Woude GF, Berens ME. Future Oncol. 2012 Nov;8(11):1397-400. doi: 10.2217/fon.12.130.
The small GTPase RhoG mediates glioblastoma cell invasion. Kwiatkowska A, Didier S, Fortin S, Chuang Y, White T, Berens ME, Rushing E, Eschbacher J, Tran NL, Chan A, Symons M. Mol Cancer. 2012 Sep 11;11:65. doi: 10.1186/1476-4598-11-65.
Specification, annotation, visualization and simulation of a large rule-based model for ERBB receptor signaling. Creamer MS, Stites EC, Aziz M, Cahill JA, Tan CW, Berens ME, Han H, Bussey KJ, Von Hoff DD, Hlavacek WS, Posner RG. BMC Syst Biol. 2012 Aug 22;6:107. doi: 10.1186/1752-0509-6-107.
Nakada M, Anderson EM, Demuth T, Nakada S, Reavie LB, Drake KL, Hoelzinger DB, Berens ME., The phosphorylation of ephrin-B2 ligand promotes glioma cell migration and invasion Int J Cancer 126(5):1155-65 2010
Kevin Maupin, Arkadeep Sinha, Jeremy Miller, Julianna Ross, Vincent Paulino, Venkat Keshamouni, Nhan Tran, Michael Berens, Craig Webb, Brian B. Haab. , Glycosylation alterations associated with pancreatic cancer EMT probed using gene expression in three model systems. PLoS One Sep 27;5(9):e13002 2010
Loftus, JC, Yang Z, Tran NL, Kloss J, Viso C, Berens ME, Lipinski CA., The Pyk2 FERM domain as a target to inhibit glioma migration Mol Cancer Ther 1505-14 2009
Mikkelsen T, Brodie C, Finniss S, Berens ME, Rennert JL, Nelson K, Lemke N, Brown SL, Hahn D, Neuteboom B, Goodman SL., Radiation sensitization of glioblastoma by cilengitide has unanticipated schedule-dependency Int J Cancer 24(11):2719-27 2009
Kislin KL, McDonough WS, Eschbacher JM, Armstrong BA, Berens ME, NHERF-1: modulator of glioblastoma cell migration and invasion Neoplasia, 11(4):377-87 2009
Salhia B, Tran NL, Chan A, Wolf A, Nakada M, Rutka F, Ennis M, McDonough WS, Berens ME, Symons M, Rutka JT, The guanine nucleotide exchange factors Trio, Ect2, and Vav3 mediate the invasive behavior of glioblastoma Am. J. Pathol, 173(6):1828-38. 2008
Lipinski CA, Tran NL, Viso C, Kloss J, Yang Z, Berens ME, Loftus JC. , Extended survival of Pyk2 or FAK deficient orthotopic glioma xenografts. J Neurooncol., 90(2):181-9 2008
Watts GS, Tran NL, Berens ME, Bhattacharyya AK, Nelson MA, Montgomery EA, Sampliner RE., Identification of Fn14/TWEAK receptor as a potential therapeutic target in esophageal adenocarcinoma. Int J Cancer Nov 15;121(10):2132-9. 2007
Winkles J.A., N.L. Tran, S.A.N. Brown, N. Stains, H.E. Cunliffe, M.E. Berens., Role of TWEAK and Fn14 in tumor biology. Frontiers in Bioscience 12, 2761-2771 2007
Tran N.L., W.S. McDonough, B.A. Savitch, S.P. Fortin, J.A. Winkles, M. Symons, M. Nakada, H.E. Cunliffe, G. Hostetter, D.B. Hoelzinger, J.L. Rennert, J.S. Michaelson, L.C. Burkly, C.A. Lipinski, J.C. Loftus, L. Mariani, M.E. Berens, Fn14 receptor activation induces Fn14 expression and malignant glioma progression via Rac1 and NF-?B. Cancer Res 66(19):9535-42. 2006
Lipinski Ca, Tran NL, Dooley A, Pang YP, Rohl C, Kloss J, Yang Z, McDonough W, Craig D, Berens ME, Loftus JC., Critical role of the FERM domain in Pyk2 stimulated glioma cell migration. Biochem Biophys Res Commun 349(3):939-47 2006
Salhia B, Tran NL*, Symons M, Winkles JA, Rutka JT, Berens ME (*contributed equally to the work)., Molecular Pathways Triggering Glioma Cell Invasion. Expert Opinions in Molecular Diagnostics. Expert Rev Mol Diagn 6(4):613-26 2006
Tran N.L., W.S. McDonough, B.A. Savitch, S.P. Fortin, J.A. Winkles, M. Symons, M. Nakada, H.E. Cunliffe, G. Hostetter, D.B. Hoelzinger, J.L. Rennert, J.S. Michaelson, L.C. Burkly, C.A. Lipinski, J.C. Loftus, L. Mariani, M.E. Berens, Increased Fibroblast Growth Factor-Inducible 14 Expression Levels Promote Glioma Cell Invasion via Rac1 and Nuclear Factor-{kappa}B and Correlate with Poor Patient Outcome Cance Res Oct 1; 66(19):9535-42. 2006
Salhia B, Tran NL, Symons M, Winkles JA, Rutka JT, Berens ME. , Triggering Glioma Cell Invasion. Expert Review of Molecular Diagnostics 6(4):613-26 2006
Salhia B, Rutten F, Nakada M, Beaudry C, Berens M, Kwan A, Rutka JT. , Inhibition of Rho-kinase affects astrocytoma morphology, motility and invasion through activation of Rac1 Cancer Research 65(19):8792-800 2005
McDonough WS* Tran NL*, Berens ME (*contributed equally to the work). , Regulation of glioma cell motility by serine phosphorylated P311 Neoplasia 7(9):862-72 2005
Nakada M, Niska JA, Tran NL, McDonough WS, Berens ME. , EphB2/R-Ras Signaling Regulates Glioma Cell Adhesion, Growth, and Invasion Am J Pathol 167: 565-576. 2005
Lipinski CA, Tran NL, Menashi E, Rohl C, Kloss J, Bay RC, Berens ME, Loftus JC., The tyrosine kinase Pyk2 promotes migration and invasion of glioma cells. Neoplasia 7(5):435-45 2005
Tran NL, McDonough WS, Savitch BA, Sawyer TS, Winkles JA, Berens ME. , The TWEAK-Fn14 signaling system regulates Glioma cell survival via NFKB pathway activation and Bcl-xL/Bcl-w expression. J Biol Chem 280(5):3483-92. 2005
Baral C., Chancellor K., Tran N., Joy A., Berens ME, A Knowledge based approach for representing and reasoning about signaling networks. Bioinformatics 20 Suppl 1:I15-I22. 2004
Chuang YY*, Tran NL*, Rusk N, Nakada M, Berens ME, Symons M. *These authors contributed equally to the work., Role of synaptojanin 2 in glioma cell migration and invasion. Cancer Res 64(22):8271-5. 2004
Lipinski CA, Tran NL, Bay RC, Kloss J, McDonough WS, Beaudry C, Berens ME, Loftus, JC. , Differential Role of PYK2 and FAK in Determining Glioblastoma Migration and Prolifteration Mol. Cancer Res (1),323-332 2003
Giese A, Bjerkvig R, Berens ME, Westphal M., Cost of migration: invasion of malignant gliomas and implications for treatment J Clin Oncol 21:1624-1636 2003
Joy, A., Beaudry C.E., Tran N.L., Ponce, F.A., Holz, D.R., Demuth, T., Berens, ME. , Migrating Glioma Cells Activate the PI3K Pathway and Display Decreased Susceptibility to Apoptosis J. Cell Sci. 116(Pt21):4409-4417 2003
Lipinski CA, Tran NL, Bay C, Kloss J, McDonough WS, Beaudry C, Berens ME, Loftus JC. , Differential role of proline-rich tyrosine kinase 2 and focal adhesion kinase in determining glioblastoma migration and proliferation. Mol Cancer Res 1:323-332 2003
Tran NL, McDonough WS, Donohue PJ, Winkles JA, Berens TJ, Ross KR, Hoelzinger DB, Beaudry C, Coons SW, Berens ME., The human Fn14 receptor gene is up-regulated in migrating glioma cells in vitro and overexpressed in advanced glial tumors. Am J Pathol 162(4):1313-1321 2003
Yoshizato K, Zapf S, Westphal M, Berens ME, Giese A. , hromboxane synthase inhibitors induce apoptosis in migration-arrested glioma cells Neurosurgery 50:343-354. 2002
Deisboeck TS, Berens ME, Kansal AR, Torquato S, Stemmer-Rachamimov AO, Chiocca EA., Pattern of self-organization in tumour systems: complex growth dynamics in a novel brain tumour spheroid model. Cell Prolif 34:115-134 2001
Mariani L, Beaudry C, McDonough WS, Hoelzinger DB, Demuth T, Ross KR, Berens T, Coons SW, Watts G, Trent JM, Wei JS, Giese A, Berens ME, Glioma cell motility is associated with reduced transcription of proapoptotic and proliferation genes: a cDNA microarray analysis J NeuroOncol 53:161-176 2001
Mariani L, Beaudry C, McDonough WS, Hoelzinger DB, Kaczmarek E, Ponce F, Coons SW, Giese A, Seiler RW, Berens ME, Death-associated protein 3 (Dap-3) is overexpressed in invasive glioblastoma cells in vivo and in glioma cell lines with induced motility phenotype in vitro Clin Cancer Res 7:2480-2489 2001
Mariani L, McDonough WS, Hoelzinger DB, Beaudry C, Kaczmarek E, Coons SW, Giese A, Moghaddam M, Seiler RW, Berens ME, Identification and validation of P311 as a glioblastoma invasion gene using laser capture microdissection Cancer Res 61:4190-4196 2001
Bittner, M., Meltzer, P., Chen, Y., Jiang, Y., Seftor, M., Hendrix, M., Radmacher, R., Simon, R., Yakhini, Z., Ben-Dor, A., Sampas, N., Dougherty, E. R., Wang, E., Marincola, F., Gooden, G., Lueders, J., Glatfelter, A., Pollock, P., Carpten, J., Gillanders, E., Leja, D., Dietrich, K., Beaudry, C., Berens, M., Alberts, D., Sondak, V., Hayward, N., Trent, J. M.. , Molecular classification of cutaneous malignant melanoma by gene expression profiling. Nature 406, 536-540 2000