Robert Wechsler-Reya, Ph.D.

Robert Wechsler-Reya's Research Focus

Brain Cancer, Childhood Diseases

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).
 

Education

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)
 

Other Affiliations

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.
July 2012 
 

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


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Publications

mTOR complex 2 is required for the development of prostate cancer induced by Pten loss in mice.

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

N-myc alters the fate of preneoplastic cells in a mouse model of medulloblastoma.

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

Stem cells and the origin and propagation of brain tumors.

Emmenegger BA, Wechsler-Reya RJ

J Child Neurol 2008 Oct ;23(10):1172-8

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Tumor necrosis factor overcomes immune evasion in p53-mutant medulloblastoma.

Garancher A, Suzuki H, Haricharan S, Chau LQ, Masihi MB, Rusert JM, Norris PS, Carrette F, Romero MM, Morrissy SA, Skowron P, Cavalli FMG, Farooq H, Ramaswamy V, Jones SJM, Moore RA, Mungall AJ, Ma Y, Thiessen N, Li Y, Morcavallo A, Qi L, Kogiso M, Du Y, Baxter P, Henderson JJ, Crawford JR, Levy ML, Olson JM, Cho YJ, Deshpande AJ, Li XN, Chesler L, Marra MA, Wajant H, Becher OJ, Bradley LM, Ware CF, Taylor MD, Wechsler-Reya RJ

Nat Neurosci 2020 May 18 ;

Zika Virus Targets Glioblastoma Stem Cells through a SOX2-Integrin α<sub>v</sub>β<sub>5</sub> Axis.

Zhu Z, Mesci P, Bernatchez JA, Gimple RC, Wang X, Schafer ST, Wettersten HI, Beck S, Clark AE, Wu Q, Prager BC, Kim LJY, Dhanwani R, Sharma S, Garancher A, Weis SM, Mack SC, Negraes PD, Trujillo CA, Penalva LO, Feng J, Lan Z, Zhang R, Wessel AW, Dhawan S, Diamond MS, Chen CC, Wechsler-Reya RJ, Gage FH, Hu H, Siqueira-Neto JL, Muotri AR, Cheresh DA, Rich JN

Cell Stem Cell 2020 Feb 6 ;26(2):187-204.e10

Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy.

Čančer M, Hutter S, Holmberg KO, Rosén G, Sundström A, Tailor J, Bergström T, Garancher A, Essand M, Wechsler-Reya RJ, Falk A, Weishaupt H, Swartling FJ

Cell Stem Cell 2019 Dec 5 ;25(6):855-870.e11

Recurrent noncoding U1 snRNA mutations drive cryptic splicing in SHH medulloblastoma.

Suzuki H, Kumar SA, Shuai S, Diaz-Navarro A, Gutierrez-Fernandez A, De Antonellis P, Cavalli FMG, Juraschka K, Farooq H, Shibahara I, Vladoiu MC, Zhang J, Abeysundara N, Przelicki D, Skowron P, Gauer N, Luu B, Daniels C, Wu X, Forget A, Momin A, Wang J, Dong W, Kim SK, Grajkowska WA, Jouvet A, Fèvre-Montange M, Garrè ML, Nageswara Rao AA, Giannini C, Kros JM, French PJ, Jabado N, Ng HK, Poon WS, Eberhart CG, Pollack IF, Olson JM, Weiss WA, Kumabe T, López-Aguilar E, Lach B, Massimino M, Van Meir EG, Rubin JB, Vibhakar R, Chambless LB, Kijima N, Klekner A, Bognár L, Chan JA, Faria CC, Ragoussis J, Pfister SM, Goldenberg A, Wechsler-Reya RJ, Bailey SD, Garzia L, Morrissy AS, Marra MA, Huang X, Malkin D, Ayrault O, Ramaswamy V, Puente XS, Calarco JA, Stein L, Taylor MD

Nature 2019 Oct ;574(7780):707-711

Biallelic loss of <i>GNAS</i> in a patient with pediatric medulloblastoma.

Tokita MJ, Nahas S, Briggs B, Malicki DM, Mesirov JP, Reyes IAC, Farnaes L, Levy ML, Kingsmore SF, Dimmock D, Crawford JR, Wechsler-Reya RJ

Cold Spring Harb Mol Case Stud 2019 Oct ;5(5)

Nilotinib, an approved leukemia drug, inhibits smoothened signaling in Hedgehog-dependent medulloblastoma.

Chahal KK, Li J, Kufareva I, Parle M, Durden DL, Wechsler-Reya RJ, Chen CC, Abagyan R

PLoS One 2019 ;14(9):e0214901

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