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Pedro R. Lowenstein, M.D., Ph.D.
Professor of Neurosurgery
Professor of Cell and Developmental Biology
pedrol@umich.edu


Current Research Activity

The focus of my research program is to discover the cellular, molecular, and mathematical basis underlying the growth patterns of malignant brain tumors, the molecular and cellular mechanisms that mediate tumor immune escape and the interactions between cancer cells with the tumor microenvironment, in both experimental models and in human patients suffering from malignant brain tumors. We have shown that galectin-1 knockdown in cancer cells causes the eradication of intracranial glioma in RAG1-/- mice lacking mature B- and T-cells by sensitizing tumor cells to NK cytotoxicity. Conversely, in NK cell depleted RAG1-/- mice, and severely immunocompromised NOD-scid IL2Rg null mice, galectin-1 deficient glioma cells progress killing the host with 100% efficiency. C57BL/6J mice with intact B- and T-cells enable galectin-1 deficient glioma growth only when NK cells are depleted. Our data indicate that adaptive immunity is not required for galectin-1 deficient glioma rejection. We are investigating therapeutic galectin-1 suppression to improve outcomes in patient survival by heightening NK immune surveillance.

a) “Endogeous glioma models:  use of lentivirus vectors to express genetic
lesions encountered in human tumors: role in tumorigenesis, invasion and the immune microenvironment.”

b) “Role of Galectin 1 signaling in glioma models: role in cancer cells’ invasion, tumor progression and NK cells’ mediated cytotoxicity.”

c) “Human Glioblastoma Stem Cells: investigations in human GBM specimens and isolated human GBM stem cells in culture. Immune mediated mechanisms in GBM stem cells’ migration.” 

d) “Role of angiogenesis in brain tumor invasion and immune cell migration: molecular and cellular mechanisms”

 


Recent Selected Publications

Sanderson NS, Puntel M, Kroeger KM, Bondale NS, Swerdlow M, Iranmanesh N, Yagita H, Ibrahim A, Castro MG, Lowenstein PR.  (2012) Cytotoxic immunological synapses do not restrict the action of interferon-γ to antigenic target cells.  The Proceedings of the National Academy of Sciences, USA, 2012 May 15: 109(20):  7835-40.  Epub 2012 April 30.  PMCID: PMC3356634

Zirger JM, Puntel M, Bergeron J, Wibowo M, Moridzadeh R, Bondale N, Barcia C, Kroeger KM, Liu C, Castro MG, Lowenstein PR. (2012) Immune-mediated Loss of Transgene Expression From Virally Transduced Brain Cells Is Irreversible, Mediated by IFNγ, Perforin, and TNFα, and due to the Elimination of Transduced Cells. Molecular Therapy 2012 Jan 10:808-819. Epub 2012 Jan 10.  PMCID: PMC3321600

King GD, Muhammad AG, Larocque D, Kelson KR, Xiong W, Liu C, Sanderson NS, Kroeger KM, Castro MG, Lowenstein PR. (2011) Combined Flt3L/TK gene therapy induces immunological surveillance which mediates an immune response against a surrogate brain tumor neo-antigen. Molecular Therapy, 19:1793-801.  PMCID: PMC3188756

Puntel M, Barrett R, Sanderson NS, Kroeger KM, Bondale N, Wibowo M, Kennedy S, Liu C, Castro MG, Lowenstein PR. (2011) Identification and visualization of CD8+ T cell mediated IFN-γ signaling in target cells during an antiviral immune response in the brain. PLoS One, 6:e23523.  PMCID: PMC3163574

Larocque D, Sanderson NRS, Bergeron J, Curtin J, Girton J, Wibowo M, Bondale N, Kroeger KM, Yang J, Lacayo LM, Reyes KC, Farrokh C, Pechnick RN, Castro MG, Lowenstein PR, (2010) Exogenous fms-like tyrosine kinase 3 ligand overrides brain immune privilege and facilitates recognition of a neo-antigen without causing autoimmune neuropathology. The Proceedings of the National Academy of Sciences, USA, 107(32):14443-14448. Epub July 26, 2010.  PMCID:  PMC2922551.

Yang J, Sanderson N, Wawrowsky K, Castro MG, Lowenstein PR. (2010) Kupfer-type immunological synapse characteristics do not predict anti-brain tumor cytolytic T-cell functions in vivo. The Proceedings of the National Academy of Sciences, USA, 107(10):4716-4721. Epub Jan 19, 2010. PMCID:  PMC2842057.

Barcia C Jr, Gomez A, Gallego-Sanchez JM, Perez-Valles A, Castro MG, Lowenstein PR, Barcia C Sr, Herrero M-T. (2009) Infiltrating CTLs in human glioblastoma establish immunological synapses with tumorigenic cells. American Journal of Pathology, 175:786-798.  Portrayed on the cover.  PMCID: PMC2716973.

Barcia C, Wawrowsky K, Barrett R, Liu C, Castro MG, Lowenstein PR. (2008) In vivo polarization of IFN-{gamma} at Kupfer and non-Kupfer immunological synapses during the clearance of virally infected brain cells. Journal of Immunology, 180:1344-1352.  PMCID: PMC2629497.

Barcia C, Gomez A, de Pablos V, Fernandez-Villalba E, Liu C, Kroeger KM, Martin J, Barreiro AF, Castro MG, Lowenstein PR, Herrero MT. (2008) CD20, CD3 and CD40 ligand microclusters segregate three-dimensionally in vivo at B Cell-T Cell immunological synapses after viral immunity in primate brain. Journal of Virology, 82:9978-9993.   PMCID: PMC2566292.

Barcia C, Thomas CE, Curtin JF, King GD, Wawrowsky K, Candolfi M, Xiong WD, Liu C, Kroeger K, Boyer O, Kupiec-Weglinski J, Klatzmann D, Castro MG, Lowenstein PR. (2006) In Vivo mature immunological synapses forming SMACs mediate clearance of virally infected astrocytes from the brain. Journal of Experimental Medicine, 203:2095-2107.  Work portrayed on journal cover, highlighted in the journal; reviewed by Science, 313[issue 5790, August 25, 2006] p. 1020; reviewed by Cell [October 20, 2006], and Journal of Cell Biology [September 11, 2006]; cited in Faculty of 1000 Medicine.  PMCID: PMC1997281.

Iannacone M, Sitia G, Isogawa M, Marchese P, Castro MG, Lowenstein PR, Chisari FV, Ruggeri ZM, Guidotti LG (2005) Platelets mediate cytotoxic T lymphocyte-induced liver damage. Nature Medicine 11(11):1167-1169.  PMCID:  PMC2908083.

Grande-Perez A, Lazaro E, Lowenstein PR, Domingo E, Manrubia SC. (2005) Suppression of viral    infectivity through lethal defection. The Proceedings of the National Academy of Science USA, 102: 4448-4452.  PMCID: PMC555496

Grande-Perez A, Sierra S, Castro MG, Domingo E, Lowenstein PR. (2002) Molecular indetermination in the transition to error catastrophe: systematic elimination of lymphocytic choriomeningitis virus through mutagenesis does not correlate linearly with large increases in mutant spectrum complexity.  The Proceedings of the National Academy of Sciences, USA, 99: 12938-12943.  PMCID: PMC130564.

 


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