David H Gutmann

Ludwig Institute for Cancer Research, La Jolla, California, United States

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Publications (413)2505.17 Total impact

  • Sarah D Ackerman, Cynthia Garcia, Xianhua Piao, David H Gutmann, Kelly R Monk
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    ABSTRACT: In the vertebrate central nervous system, myelinating oligodendrocytes are postmitotic and derive from proliferative oligodendrocyte precursor cells (OPCs). The molecular mechanisms that govern oligodendrocyte development are incompletely understood, but recent studies implicate the adhesion class of G protein-coupled receptors (aGPCRs) as important regulators of myelination. Here, we use zebrafish and mouse models to dissect the function of the aGPCR Gpr56 in oligodendrocyte development. We show that gpr56 is expressed during early stages of oligodendrocyte development. In addition, we observe a significant reduction of mature oligodendrocyte number and myelinated axons in gpr56 zebrafish mutants. This reduction results from decreased OPC proliferation, rather than increased cell death or altered neural precursor differentiation potential. Finally, we show that these functions are mediated by Gα12/13 proteins and Rho activation. Together, our data establish Gpr56 as a regulator of oligodendrocyte development.
    Nature Communications 01/2015; 6:6122. · 10.74 Impact Factor
  • The Lancet Neurology 01/2015; 14(1):30-31. · 21.82 Impact Factor
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    ABSTRACT: Children with neurofibromatosis type 1 (NF1) develop optic pathway gliomas, which result from impaired NF1 protein regulation of Ras activity. One obstacle to the implementation of biologically targeted therapies is an incomplete understanding of the individual contributions of the downstream Ras effectors (mitogen-activated protein kinase kinase [MEK], Akt) to optic glioma maintenance. This study was designed to address the importance of MEK and Akt signaling to Nf1 optic glioma growth. Primary neonatal mouse astrocyte cultures were employed to determine the consequence of phosphatidylinositol-3 kinase (PI3K)/Akt and MEK inhibition on Nf1-deficient astrocyte growth. Nf1 optic glioma-bearing mice were used to assess the effect of Akt and MEK inhibition on tumor volume, proliferation, and retinal ganglion cell dysfunction. Both MEK and Akt were hyperactivated in Nf1-deficient astrocytes in vitro and in Nf1 murine optic gliomas in vivo. Pharmacologic PI3K or Akt inhibition reduced Nf1-deficient astrocyte proliferation to wild-type levels, while PI3K inhibition decreased Nf1 optic glioma volume and proliferation. Akt inhibition of Nf1-deficient astrocyte and optic glioma growth reflected Akt-dependent activation of mammalian target of rapamycin (mTOR). Sustained MEK pharmacologic blockade also attenuated Nf1-deficient astrocytes as well as Nf1 optic glioma volume and proliferation. Importantly, these MEK inhibitory effects resulted from p90RSK-mediated, Akt-independent mTOR activation. Finally, both PI3K and MEK inhibition reduced optic glioma-associated retinal ganglion cell loss and nerve fiber layer thinning. These findings establish that the convergence of 2 distinct Ras effector pathways on mTOR signaling maintains Nf1 mouse optic glioma growth, supporting the evaluation of pharmacologic inhibitors that target mTOR function in future human NF1-optic pathway glioma clinical trials. © The Author(s) 2014. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
    Neuro-Oncology 12/2014; · 5.29 Impact Factor
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    ABSTRACT: With increased internet accessibility worldwide, it is now possible to assemble individuals with rare diseases through web-based patient registries. However, the validity of participant-reported medical diagnoses is unknown. The objective of this study was to evaluate the accuracy of participant-reported Neurofibromatosis Type 1 (NF1) diagnoses among participants in the NF1 Patient Registry Initiative (NPRI). Subjects enrolled in the NPRI from 5/17/2011 to 7/7/2014 were included. Medical records (MRs) were obtained for participants who returned medical record release forms (MRRFs) during the study period. Participants were classified as having definite, probable, suspected, or no NF1 diagnosis based on MR information. To assess whether a returned MRRF served as a reliable marker of MR-documented NF1, we calculated the positive predictive value (PPV) as the proportion of individuals with MR-documented NF1 among those from whom MRs were obtained. We further examined whether a returned MRRF predicted the number of reported NF1 clinical signs in multivariable linear regression analyses. A total of 1456 individuals were included in the analyses. Of 416 individuals who returned MRRFs, 205 MRs were reviewed within the study period. The PPV ranged from 72.0 to 98.5% when including definite or definite/probable/suspected cases, respectively. The mean number of reported NF1 clinical signs was similar between those who returned (mean=3.3±1.2) and did not return (mean=3.2±1.3) their MRRFs. MRRF return was not a significant predictor of the number of NF1 clinical signs after adjusting for covariates. These data strongly suggest that individuals enrolling in the NPRI accurately report their NF1 diagnosis. Copyright © 2014 Elsevier Inc. All rights reserved.
    Contemporary Clinical Trials 12/2014; · 1.99 Impact Factor
  • David H Gutmann
    Neuro-Oncology 12/2014; · 5.29 Impact Factor
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    ABSTRACT: One of the potential etiologies for non-familial Neurofibromatosis Type 1 (NF1) is increasing parental age. We sought to evaluate recent evidence for parental age effects in NF1 in a large study. Individuals with NF1 and a comparison group from the U.S. general population born between 1994 and 2012 were ascertained from the NF1 Patient Registry Initiative (NPRI) and the National Center for Vital Statistics, respectively. Multiple linear regression analysis was employed to identify differences between familial NF1, non-familial NF1, and U.S. population subjects in the mean parental ages at the time of the birth of offspring in each group. In addition, we also evaluated the effect of parental age on NF1 offspring with and without a pediatric brain tumor history. A total of 313 subjects from the NPRI (including 99 brain tumor cases) matched by birth year at a 1:3 ratio to U.S. general population births (n = 939) were included. Compared to the U.S. general population and familial NF1 cases, the mean paternal age for non-familial NF1 cases was 4.34 years (95 % CI 3.23-5.46, p ≤ 0.0001) and 3.39 years (95 % CI 1.57-5.20, p ≤ 0.0001) older, respectively, after adjusting for birth year. A similar pattern was observed for maternal age. There were no statistically significant differences in the mean maternal or paternal ages between NF1 offspring with and without a pediatric brain tumor. In conclusion, these data support a parental age effect for non-familial NF1 cases, but not for pediatric brain tumors in NF1.
    Familial Cancer 12/2014; · 1.94 Impact Factor
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    ABSTRACT: Neurofibromatosis type 1 (NF1) was the first RASopathy and is now one of many RASopathies that are caused by germline mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) pathway. Their common underlying pathogenetic etiology causes significant overlap in phenotypic features which includes craniofacial dysmorphology, cardiac, cutaneous, musculoskeletal, GI and ocular abnormalities, and a predisposition to cancer. The proceedings from the symposium "Recent Developments in Neurofibromatoses (NF) and RASopathies: Management, Diagnosis and Current and Future Therapeutic Avenues" chronicle this timely and topical clinical translational research symposium. The overarching goal was to bring together clinicians, basic scientists, physician-scientists, advocate leaders, trainees, students and individuals with Ras pathway syndromes to discuss the most state-of-the-art basic science and clinical issues in an effort to spark collaborations directed towards the best practices and therapies for individuals with RASopathies. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 11/2014; · 2.05 Impact Factor
  • David H Gutmann
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    ABSTRACT: Plexiform neurofibromas are one of the most common tumors encountered in individuals with the neurofibromatosis type I (NF1) cancer predisposition syndrome. In this issue of Cancer Cell, Chen and colleagues define the cell of origin for murine Nf1 plexiform neurofibroma and leverage this finding to develop a platform for preclinical drug evaluation. Copyright © 2014 Elsevier Inc. All rights reserved.
    Cancer cell. 11/2014; 26(5):596-599.
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    ABSTRACT: Identifying modifiers of glioma risk in patients with type 1 neurofibromatosis (NF1) could help support personalized tumor surveillance, advance understanding of gliomagenesis and potentially identify novel therapeutic targets. Here we report genetic polymorphisms in the human adenylate cyclase gene ADCY8 which correlate with glioma risk in NF1 in a sex-specific manner, elevating risk in females while reducing risk in males. This finding extends earlier evidence of a role for cAMP in gliomagenesis based on results in a genetically engineered mouse model (Nf1 GEM). Thus, sexually dimorphic cAMP signaling might render males and females differentially sensitive to variation in cAMP levels. Using male and female Nf1 GEM, we found significant sex differences exist in cAMP regulation and in the growth promoting effects of cAMP suppression. Overall, our results establish a sex-specific role for cAMP regulation in human gliomagenesis, specifically identifying ADCY8 as a modifier of glioma risk in NF1.
    Cancer Research 11/2014; · 9.28 Impact Factor
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    ABSTRACT: Plexiform neurofibromas (PNs) are benign peripheral nerve sheath tumors that arise in one-third of individuals with neurofibromatosis type 1 (NF1). They may cause significant disfigurement, compression of vital structures, neurologic dysfunction, and/or pain. Currently, the only effective management strategy is surgical resection. Converging evidence has demonstrated that the NF1 tumor suppressor protein, neurofibromin, negatively regulates activity in the mammalian Target of Rapamycin pathway.
    Neuro-Oncology 10/2014; · 5.29 Impact Factor
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    ABSTRACT: Most meningiomas are benign, but some clinical-aggressive tumors exhibit brain invasion and cannot be resected without significant complications. To identify molecular markers for these clinically-aggressive meningiomas, we performed microarray analyses on 24 primary cultures from 21 meningiomas and 3 arachnoid membranes. Using this approach, increased transglutaminase 2 (TGM2) expression was observed, which was subsequently validated in an independent set of 82 meningiomas by immunohistochemistry. Importantly, the TGM2 expression level was associated with increasing WHO malignancy grade as well as meningioma recurrence. Inhibition of TGM2 function by siRNA or cystamine induced meningioma cell death, which was associated with reduced AKT phosphorylation and caspase-3 activation. Collectively, these findings suggest that TGM2 expression increases as a function of malignancy grade and tumor recurrence and that inhibition of TGM2 reduces meningioma cell growth.
    PLoS ONE 09/2014; 9(9):e108228. · 3.53 Impact Factor
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    ABSTRACT: Children with the neurofibromatosis type 1 (NF1) tumor predisposition syndrome are prone to the development of optic pathway gliomas resulting from biallelic inactivation of the NF1 gene. Recent studies have revealed the presence of other molecular alterations in a small portion of these NF1-associated brain tumors. The purpose of this study was to leverage Nf1 genetically engineered mouse strains to define the functional significance of these changes to optic glioma biology.
    Neuro-Oncology 09/2014; · 5.29 Impact Factor
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    ABSTRACT: Cellular schwannoma is an uncommon, but well-recognized, benign peripheral nerve sheath tumor, which can be misdiagnosed as malignant peripheral nerve sheath tumor. To develop consensus diagnostic criteria for cellular schwannoma, we reviewed 115 malignant peripheral nerve sheath tumor and 26 cellular schwannoma cases from two institutions. Clinical data were retrieved from the electronic medical records, and morphologic features, maximal mitotic counts, Ki67 labeling indices, and immunohistochemical profiles (SOX10, SOX2, p75NTR, p16, p53, EGFR, and neurofibromin) were assessed. Several features distinguish cellular schwannoma from malignant peripheral nerve sheath tumor. First, in contrast to patients with malignant peripheral nerve sheath tumor, no metastases or disease-specific deaths were found in patients with cellular schwannoma. More specifically, 5-year progression-free survival rates were 100 and 18%, and 5-year disease-specific survival rates were 100 and 32% for cellular schwannoma and malignant peripheral nerve sheath tumor, respectively. Second, the presence of Schwannian whorls, a peritumoral capsule, subcapsular lymphocytes, macrophage-rich infiltrates, and the absence of fascicles favored the diagnosis of cellular schwannoma, while the presence of perivascular hypercellularity, tumor herniation into vascular lumens, and necrosis favor malignant peripheral nerve sheath tumor. Third, complete loss of SOX10, neurofibromin or p16 expression, or the presence of EGFR immunoreactivity was specific for malignant peripheral nerve sheath tumor (P<0.001 for each). Expression of p75NTR was observed in 80% of malignant peripheral nerve sheath tumors compared with 31% of cellular schwannomas (P<0.001). Fourth, Ki-67 labeling indices ≥20% were highly predictive of malignant peripheral nerve sheath tumor (87% sensitivity and 96% specificity). Taken together, the combinations of these histopathological and immunohistochemical features provide useful criteria to distinguish between malignant peripheral nerve sheath tumor and cellular schwannoma with high sensitivity and specificity. Additional retrospective and prospective multicenter studies with larger data sets will be required to validate these findings.Modern Pathology advance online publication, 5 September 2014; doi:10.1038/modpathol.2014.109.
    Modern Pathology 09/2014; · 6.36 Impact Factor
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    American Journal of Medical Genetics Part A 09/2014; · 2.30 Impact Factor
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    ABSTRACT: Expression profiling of distinct central nervous system (CNS) cell populations has been employed to facilitate disease classification and to provide insights into the molecular basis of brain pathology. One important cell type implicated in a wide variety of CNS disease states is the resident brain macrophage (microglia). In these studies, microglia are often isolated from dissociated brain tissue by flow sorting procedures [fluorescence-activated cell sorting (FACS)] or from postnatal glial cultures by mechanic isolation. Given the highly dynamic and state-dependent functions of these cells, the use of FACS or short-term culture methods may not accurately capture the biology of brain microglia. In the current study, we performed RNA-sequencing using Cx3cr1+/GFP labeled microglia isolated from the brainstem of 6-week-old mice to compare the transcriptomes of FACS-sorted versus laser capture microdissection (LCM). While both isolation techniques resulted in a large number of shared (common) transcripts, we identified transcripts unique to FACS-isolated and LCM-captured microglia. In particular, ∼50% of these LCM-isolated microglial transcripts represented genes typically associated with neurons and glia. While these transcripts clearly localized to microglia using complementary methods, they were not translated into protein. Following the induction of murine experimental autoimmune encephalomyelitis, increased oligodendrocyte and neuronal transcripts were detected in microglia, while only the myelin basic protein oligodendrocyte transcript was increased in microglia after traumatic brain injury. Collectively, these findings have implications for the design and interpretation of microglia transcriptome-based investigations. GLIA 2014
    Glia 09/2014; · 5.47 Impact Factor
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    ABSTRACT: Inhibition of the mammalian target of rapamycin (mTOR) signaling pathway has become an attractive target for human cancer therapy. Hyperactivation of mTOR has been reported in both sporadic and syndromic (hereditary) brain tumors. In contrast to the large number of successful clinical trials employing mTOR inhibitors in different types of epithelial neoplasms, their use to treat intracranial neoplasms is more limited. In this review, we summarize the role of mTOR activation in brain tumor pathogenesis and growth relevant to new human brain tumor trials currently under way using mTOR inhibitors.
    Neuro-oncology. 08/2014;
  • Katherine E Schwetye, David H Gutmann
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    ABSTRACT: Cognitive and behavioral disorders affect nearly 80% of all children with the neurofibromatosis type 1 inherited cancer syndrome, and are among the most significant clinical manifestations for patients and their families. One of the barriers to successful therapeutic intervention is the wide spectrum of clinical phenotypic expression, ranging from visuospatial learning problems to social perceptual deficits (autism). Leveraging numerous small-animal models of neurofibromatosis type 1, several promising targets have been identified to treat the learning, attention, and autism spectrum phenotypes in this at-risk population. In this review, we provide an up-to-date summary of our current understanding of these disorders in NF1, and propose future research directions aimed at designing more effective therapeutic approaches and clinical trials.
    Expert Review of Neurotherapeutics 08/2014; · 2.96 Impact Factor
  • Angela C Hirbe, David H Gutmann
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    ABSTRACT: Neurofibromatosis type 1 is a relatively common inherited disorder. Patients have a high predisposition to develop both benign and malignant tumours. Although many manifestations of neurofibromatosis type 1 affect the nervous system, other organs and tissues can also be affected. Because of the varying features and clinical heterogeneity inherent to this disorder, patients can present to different medical and surgical specialists and, therefore, the association of clinical symptoms with neurofibromatosis type 1 might not be appreciated. Thus, for prompt diagnosis and to provide optimum care for patients with neurofibromatosis type 1, clinicians must be aware of the diverse clinical features of this disorder. We advocate a multidisciplinary approach to care, entailing a dedicated team of specialists throughout the lifetime of the patient. As our understanding of this disorder deepens through basic laboratory and clinical investigations, swift implementation of new effective treatments becomes feasible.
    The Lancet Neurology 08/2014; 13(8):834–843. · 21.82 Impact Factor
  • Corina Anastasaki, David H Gutmann
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    ABSTRACT: Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder in which affected individuals are prone to learning, attention, and behavioral problems. Previous studies in mice and flies have yielded conflicting results regarding the specific effector pathways responsible for NF1 protein (neurofibromin) regulation of neuronal function, with both cyclic AMP (cAMP)- and RAS-dependent mechanisms described. Herein, we leverage a combination of induced pluripotent stem cell (iPSC)-derived NF1-patient neural progenitor cells (NPCs) and Nf1 genetically-engineered mice to establish, for the first time, that neurofibromin regulation of cAMP requires RAS activation in human and mouse neurons. However, instead of involving RAS-mediated MEK/AKT signaling, RAS regulation of cAMP homeostasis operates through the activation of atypical Protein Kinase C (PKCζ), leading to GRK2-driven Gs inactivation. These findings reveal a novel mechanism by which RAS can regulate cAMP levels in the mammalian brain.
    Human Molecular Genetics 07/2014; · 6.68 Impact Factor
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    ABSTRACT: Glioblastoma (GBM) frequently displays amplification and/or mutation of the epidermal growth factor receptor (EGFR) gene. Highlighting the importance of EGFR in the pathogenesis of GBM, aberrant EGFR (ΔEGFR, also known as EGFRvIII) confers a variety of biological effects upon its expression, including resistance to radiation and chemotherapeutic agents, promotion of tumor cell motility and invasion, enhancement of tumorigenicity in vivo, and maintenance of GBM growth and heterogeneity. We hypothesized that this diverse oncogenic pathophysiology exerted by ΔEGFR is regulated, in part, through the modulation of microRNA (miR) activity, widely shown to be involved in many biological processes including cancer initiation, maintenance and progression.
    Neuro-Oncology 07/2014; 16 Suppl 3:iii14-iii15. · 5.29 Impact Factor

Publication Stats

13k Citations
2,505.17 Total Impact Points

Institutions

  • 2014
    • Ludwig Institute for Cancer Research
      La Jolla, California, United States
  • 2006–2014
    • Otto-von-Guericke-Universität Magdeburg
      • Institute for Neuropathology
      Magdeburg, Saxony-Anhalt, Germany
    • Duke University Medical Center
      • Department of Pharmacology and Cancer Biology
      Durham, NC, United States
  • 1995–2014
    • Washington University in St. Louis
      • • Department of Neurology
      • • Department of Pathology and Immunology
      • • Department of Pediatrics
      San Luis, Missouri, United States
  • 2013
    • Guy's and St Thomas' NHS Foundation Trust
      Londinium, England, United Kingdom
  • 1994–2013
    • University of Washington Seattle
      • • Department of Neurology
      • • Division of General Internal Medicine
      • • Department of Pathology
      Seattle, WA, United States
  • 2012
    • University of Texas Southwestern Medical Center
      Dallas, Texas, United States
    • The Children's Hospital of Philadelphia
      • Division of Oncology
      Philadelphia, PA, United States
  • 1992–2011
    • Concordia University–Ann Arbor
      Ann Arbor, Michigan, United States
  • 2009
    • University of California, Davis
      • Department of Surgical and Radiological Sciences (VM)
      Davis, CA, United States
  • 1996–2009
    • University of Toronto
      • • Hospital for Sick Children
      • • Division of Neurology
      • • Division of Neurosurgery
      Toronto, Ontario, Canada
    • Universitair Medisch Centrum Groningen
      Groningen, Groningen, Netherlands
  • 2007–2008
    • Mayo Foundation for Medical Education and Research
      Rochester, Michigan, United States
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States
    • St. Jude Children's Research Hospital
      • Department of Developmental Neurobiology
      Memphis, TN, United States
  • 1997–2008
    • National Cancer Institute (USA)
      • • Mouse Cancer Genetics Program
      • • Laboratory of Cellular Oncology
      Maryland, United States
  • 2004–2007
    • Oregon Health and Science University
      Portland, Oregon, United States
    • Medical University of South Carolina
      Charleston, South Carolina, United States
  • 2001–2007
    • Emory University
      • • Department of Pathology and Laboratory Medicine
      • • Department of Dermatology
      Atlanta, GA, United States
    • University of Cincinnati
      Cincinnati, Ohio, United States
  • 1997–2007
    • Children's Memorial Hospital
      Chicago, Illinois, United States
  • 2000–2006
    • SickKids
      • Arthur and Sonia Labatt Brain Tumour Research Centre (BTRC)
      Toronto, Ontario, Canada
    • National Institutes of Health
      • Branch of Genetic Epidemiology
      Bethesda, MD, United States
  • 2003
    • Mount Sinai Hospital
      New York City, New York, United States
    • University of California, Los Angeles
      • Department of Medicine
      Los Angeles, CA, United States
  • 2002
    • King's College London
      Londinium, England, United Kingdom
  • 1998–2001
    • Samuel Lunenfeld Research Institute
      Toronto, Ontario, Canada
  • 1989–1997
    • Hospital of the University of Pennsylvania
      • Department of Neurology
      Philadelphia, Pennsylvania, United States
  • 1992–1994
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1991
    • University of Pennsylvania
      • Department of Neurology
      Philadelphia, PA, United States
    • University of Michigan
      • Department of Internal Medicine
      Ann Arbor, MI, United States