Robert Wechsler-Reya's Research Focus
Normal development requires a delicate balance between proliferation, differentiation, and death. When these processes become dysregulated, a cell that would normally differentiate or die may divide uncontrollably, and a tumor may result. Dr. Wechsler-Reya’s research focuses on the molecular mechanisms that regulate cell growth and tumorigenesis in the nervous system. In particular, his group studies the role of the Sonic hedgehog (Shh) signaling pathway in the development of the cerebellum and in the genesis of a brain tumor called medulloblastoma.
Robert Wechsler-Reya's Research Report
Control of Neuronal Growth and Differentiation
Proper development of the nervous system requires a balance between proliferation of neuronal precursors and differentiation of these cells into neurons. This balance is particularly striking in the case of cerebellar granule cells, the most abundant neurons in the brain and a critical component of the circuitry that controls motor coordination. When granule cell precursor proliferation is disrupted and not enough granule cells are generated, cerebellar dysfunction and ataxia may result; when granule cell differentiation fails, cells that would normally become post-mitotic continue to proliferate and may give rise to cerebellar tumors. Therefore, elucidating the molecular mechanisms that control growth and differentiation is critical for understanding both normal cerebellar development and tumorigenesis.
Our previous studies demonstrated that proliferation of granule neuron precursors (GNPs) is controlled by the secreted signaling molecule Sonic hedgehog (Shh). But the signals that cause GNPs to stop proliferating, differentiate and migrate remain a mystery. Using both primary cell culture and transgenic mouse models, we are investigating the role of fibroblast growth factors, netrins, chemokines and other signals in granule cell development.
Brain Tumor Initiation and Progression
Medulloblastoma is the most common malignant brain tumor in children. Its rapid growth and tendency to spread through the nervous system make it difficult to treat, and many of the children who develop the disease die from it. In addition, patients who survive medulloblastoma treatment often suffer cognitive deficits and have a tendency to develop other cancers later in life. Improved treatment of medulloblastoma is likely to come from a deeper understanding of the signals that control normal cerebellar development, and an appreciation of how these signals are dysregulated in tumors.
To identify such signals, we have studied an animal model of medulloblastoma – the patched mutant mouse – and screened for genes whose expression is altered in tumor cells compared to granule cell precursors, the cells from which the tumor is believed to arise. The genes whose expression changed most significantly included regulators of migration, apoptosis and differentiation, processes crucial for normal development but previously unrecognized for their role in medulloblastoma. Current studies in our lab are using retroviral gene transduction, cell transplantation and transgenic mice to elucidate the role of these genes in tumor initiation and progression.
Stem Cells and the Origin of Brain Tumors
Stem cells are likely to play a central role in cancer. Their long lifespan and extensive capacity for self-renewal make them particularly sensitive to transformation, so they may represent a cell of origin for many tumors. A number of recent studies have suggested that stem-like cells are present in human brain tumors, but the role of stem cells in brain tumor initiation has not been tested. Studies in our lab are aimed at examining the role of neural stem cells in the etiology of the cerebellar tumor medulloblastoma.
Recent studies from our lab have identified a population of neural stem cells in the postnatal cerebellum. These cells express the stem cell marker CD133, can form self-renewing "neurospheres" in culture, and can be induced to differentiate into neurons, astrocytes and oligodendrocytes both in vitro and following transplantation into the cerebellum. Our current research is directed at understanding the role of these cells in normal cerebellar development, and exploring the possibility that they might represent the cell of origin for some types of medulloblastoma.
Robert Wechsler-Reya's Bio
Dr. Wechsler-Reya's research focuses on the signals that control growth and differentiation in the cerebellum, and how these signals are dysregulated in the brain tumor medulloblastoma. As a postdoc, he demonstrated that Sonic hedgehog (Shh) is a critical mitogen for neuronal precursors in the cerebellum, and that mutations in the Shh pathway predispose to medulloblastoma by activating a mitogenic pathway that normally functions only in early development. Now in his own lab, he continues to study the relationship between brain development and brain tumor formation. His lab’s contributions include identifying N-myc as a key target of the Shh pathway in neuronal precursors and in tumor cells; discovering a novel population of neural stem cells in the neonatal cerebellum; demonstrating that both neuronal precursors and stem cells can serve as cells of origin for MB; and identifying a population of cancer stem cells that is critical for propagation of Shh-associated tumors. More recently, Dr. Wechsler-Reya and his group have begun developing new models of medulloblastoma and are using them to test novel therapeutic approaches. His work has garnered several awards, including a Kimmel Scholar Award, an Award for Excellence in Pediatrics Research from the Society for Neuro-Oncology and a Leadership Award from the California Institute for Regenerative Medicine (CIRM).
2001-2010: Associate Professor of Pharmacology and Cancer Biology, Duke University Medical Center
1997-2001: Postdoctoral Fellow, Stanford University, Neural Development
1995-1996: Postdoctoral Fellow, Wistar Institute, Molecular Oncology
1995: Ph.D., University of Pennsylvania, Immunology
1986: B.A., Harvard College, Psychology & Biology
Funding Awards and Collaborative Grants
Leadership Award from the California Institute for Regenerative Medicine (CIRM)
19th International Brain Tumor Research and Therapy Conference
A University of Toronto Hosted Conference
Niagara Falls, ON
June 21–24, 2012
"Developmental tumors of the nervous system," held in Barcelona on July 2012, as part of the 8th Forum of European Neuroscience Societies.
Honors and Recognition
2007: W.K. Joklik Award for Excellence in Basic Cancer Research
2007: DukeMed Scholar
2006: Award for Excellence in Pediatrics Research, Society for Neuro-Oncology
2003: Kimmel Scholar Award, Sidney Kimmel Foundation for Cancer Research
2003: Brain Tumor Society Research Award
2002: Children’s Brain Tumor Foundation Research Award
2000-2001: Postdoctoral Fellowship, American Cancer Society (California)
1995-1997: Postdoctoral Fellowship, Medical Research Council of Canada
1988: Award for Excellence in Scientific Writing, American Diabetes Association
1984-1985: John Harvard Scholarship for Academic Achievement of Highest Distinction
Guertin DA, Stevens DM, Saitoh M, Kinkel S, Crosby K, Sheen JH, Mullholland DJ, Magnuson MA, Wu H, Sabatini DM
Cancer Cell 2009 Feb 3 ;15(2):148-59
Kessler JD, Hasegawa H, Brun SN, Emmenegger BA, Yang ZJ, Dutton JW, Wang F, Wechsler-Reya RJ
Genes Dev 2009 Jan 15 ;23(2):157-70
Emmenegger BA, Wechsler-Reya RJ
J Child Neurol 2008 Oct ;23(10):1172-8
Householder KT, Dharmaraj S, Sandberg DI, Wechsler-Reya RJ, Sirianni RW
Sci Rep 2019 Aug 29 ;9(1):12587
Hovestadt V, Smith KS, Bihannic L, Filbin MG, Shaw ML, Baumgartner A, DeWitt JC, Groves A, Mayr L, Weisman HR, Richman AR, Shore ME, Goumnerova L, Rosencrance C, Carter RA, Phoenix TN, Hadley JL, Tong Y, Houston J, Ashmun RA, DeCuypere M, Sharma T, Flasch D, Silkov A, Ligon KL, Pomeroy SL, Rivera MN, Rozenblatt-Rosen O, Rusert JM, Wechsler-Reya RJ, Li XN, Peyrl A, Gojo J, Kirchhofer D, Lötsch D, Czech T, Dorfer C, Haberler C, Geyeregger R, Halfmann A, Gawad C, Easton J, Pfister SM, Regev A, Gajjar A, Orr BA, Slavc I, Robinson GW, Bernstein BE, Suvà ML, Northcott PA
Nature 2019 Aug ;572(7767):74-79
Structure-Activity Relationships for Itraconazole-Based Triazolone Analogues as Hedgehog Pathway Inhibitors.
Pace JR, Teske KA, Chau LQ, Dash RC, Zaino AM, Wechsler-Reya RJ, Hadden MK
J Med Chem 2019 Apr 25 ;62(8):3873-3885
Wang J, Merino DM, Light N, Murphy BL, Wang YD, Guo X, Hodges AP, Chau LQ, Liu KW, Dhall G, Asgharzadeh S, Kiehna EN, Shirey RJ, Janda KD, Taylor MD, Malkin D, Ellison DW, VandenBerg SR, Eberhart CG, Sears RC, Roussel MF, Gilbertson RJ, Wechsler-Reya RJ
Cancer Res 2019 May 1 ;79(9):2208-2219
<i>Sleeping Beauty</i> Insertional Mutagenesis Reveals Important Genetic Drivers of Central Nervous System Embryonal Tumors.
Beckmann PJ, Larson JD, Larsson AT, Ostergaard JP, Wagner S, Rahrmann EP, Shamsan GA, Otto GM, Williams RL, Wang J, Lee C, Tschida BR, Das P, Dubuc AM, Moriarity BS, Picard D, Wu X, Rodriguez FJ, Rosemarie Q, Krebs RD, Molan AM, Demer AM, Frees MM, Rizzardi AE, Schmechel SC, Eberhart CG, Jenkins RB, Wechsler-Reya RJ, Odde DJ, Huang A, Taylor MD, Sarver AL, Largaespada DA
Cancer Res 2019 Mar 1 ;79(5):905-917
Lee C, Rudneva VA, Erkek S, Zapatka M, Chau LQ, Tacheva-Grigorova SK, Garancher A, Rusert JM, Aksoy O, Lea R, Mohammad HP, Wang J, Weiss WA, Grimes HL, Pfister SM, Northcott PA, Wechsler-Reya RJ
Nat Commun 2019 Jan 18 ;10(1):332