Headshot of Pedro Lowenstein

Education

Research

The current focus of my research program is to discover the cellular, molecular, and mathematical basis underlying the growth patterns of malignant brain tumors, and the interactions between cancer cells with the tumor microenvironment, in both experimental models and in human patients suffering from malignant brain tumors.

The current focus of my research program is to discover the cellular, molecular, and mathematical basis underlying the growth patterns of malignant brain tumors, and the interactions between cancer cells with the tumor microenvironment, in both experimental models and in human patients suffering from malignant brain tumors. To do so, we are probing how brain glioma cells migrate throughout the brain and eventually kill the hosts' neurons and glial cells. Understanding the precise molecular basis of glioma tumor cell growth and invasive behavior, will uncover novel therapeutic targets aiming at inactivating the essential mechanisms used by tumors to grow and destroy normal brain tissue, and thus, kill the host. We are studying very early stages of tumor pattern formation using fluorescently labeled glioma cells in combination with in vivo multiphoton imaging technologies. We are also developing endogenous models of brain tumors induced by lentiviral vectors encoding gene products thought to cause human gliomas (e.g., PDGF, Akt and K-ras).

We have discovered that early glioma cells use the existing vascular network as a scaffold, and from there they encircle and kill normal brain cells. As we identify gene products involved in specific glioma behavior, lentiviral mediated gene expression knock-down will enable us to determine which of these play essential roles in glioma tumor formation. In addition, we are dissecting the molecular mechanisms of the anti-glioma immune response, and especially, the mechanisms that limit its clinical effectiveness. These approaches will be used to develop novel therapeutic approaches. My lab recently discovered the formation of tumor antigen specific immunological synapses between activated effector T cells and target tumor cells in an intracranial syngeneic brain tumor model; thus, my group has pioneered the development of immunological tools to be used in the implementation of Phase I clinical trials for malignant brain cancer.



Publications

Representative Publications

  1. 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. Proc Natl Acad Sci U S A. 2012 May 15; 109(20):7835-40.
  2. Larocque D, Sanderson NRS, Bergeron J, Curtin J, Girton J, Wibowo M, Bondale N, Kroeger KM, Yang J, Lacayo LM, Reyes KC, Farrokhi 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. Proceedings of the National Academy of Sciences, USA. 107(32):14443-14448. Epub July 26. PMCID: PMC2922551
  3. Yang J, Sanderson N, Wawrowsky K, Castro MG, Lowenstein PR. (2010) Kupfer-type immunological synapses are not relevant to cytolytic T-cell function in vivo.Proceedings of the National Academy of Sciences, USA 107:4716-21 Portrayed on the cover PMCID: PMC2842057
  4. 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(2):786-798 PMCID: PMC2716973
  5. Barcia C, Wawrowsky K, Barrett RJ, Liu C, Castro MG, Lowenstein PR, (2008) In vivo polarization of IFN-? at Kupfer and non-Kupfer immunological synapses during the clearance of virally infected brain cells. The Journal of Immunology, 180(3)1344-1352. Portrayed on the cover; PMCID: PMC2629497
  6. Barcia C, Thomas C, Curtin J, King G, Wawrowsky K, Candolfi M, Kroeger K, Boyer O, Kupiec-Weglinski J, Klatzmann D, Castro MG, Lowenstein PR, (2006) In Vivo mature effector immunological synapses forming supramolecular activation cluster (SMAC) mediate clearance of virally infected astrocytes from the brain. The Journal of Experimental Medicine 203(9):2095-2107 Portrayed on the cover, reviewed in detail by Science, Cell, and Faculty of 1000-Biology.
  7. Umana P, Gerdes CA, Stone D, Davis JR, Ward D, Castro MG, Lowenstein PR (2001) Efficient FLPe recombinase enables scalable production of helper-dependent adenoviral vectors with negligible helper-virus contamination. Nature Biotechnology, 19:582-585.
  8. Thomas CE, Schiedner G, Kochanek S, Castro MG, Lowenstein PR (2000) Peripheral infection with adenovirus causes unexpected long-term brain inflammation in animals injected intracranially with first generation, but not with high-capacity adenovirus vectors: towards realistic long-term neurological gene therapy for chronic diseases. Proc. Natl. Acad. Sci. U.S.A., 97:7482-7487.
  9. Dewey R, Morrissey G, Cowsill C, Stone D, Dodd NJF, Bolognani F, Southgate TD, Castro MG, Lowenstein PR, (1999) Chronic brain inflammation and persistent HSV1 TK expression in survivors of syngeneic glioma treated by adenovirus-mediated gene therapy. Nature Medicine 5,1256-63.