Peter D. Canoll, MD, PhD
My research has focused on understanding the molecular and cellular mechanisms of gliomagenesis and, on interactions between glioma cells and the brain microenvironment. By targeting glial progenitor cells in the adult brain, my laboratory has developed genetically engineered mouse models that recapitulate the histological and molecular features of human glioma. We are applying a variety of cutting edge techniques to characterize cellular alterations that accumulate in these mouse models and in human glioma tissue. I serve as the director of neuropathology and as the primary neuropathologist on all clinical trials run by the Columbia Brain Tumor Program. Over the last 14 years I have analyzed and diagnosed hundreds of brain tumors. My over-arching goal is to apply my clinical and research experience to help bridge the analysis of laboratory experiments and human disease, and to advance the development of more informative diagnosis and more effective treatments for brain tumors.
1. Receptor Tyrosine Kinases And Phosphatases In Glial Proliferation And Differentiation: During my graduate studies at NYU, I worked with Jose Musacchio and Joesph Schlessinger to identify a new family of receptor tyrosine phosphatases that are selectively expressed in the brain. I used in situ hybridization to determine the cell-specific expression patterns of several of these genes and discovered that PTPRZ (aka RPTP-beta) is expressed in glial progenitors and undergoes alternative splicing during glial differentiation. I also worked with Jim Salzer (NYU) to characterize the role of receptor tyrosine kinases (ErbB 2, 3, and 4) in glial development, and showed that neuregulins (neuron derived ligands for ErbB receptors) can control the proliferation and differentiation of oligodendrocyte progenitor cells (OPCs).
a. Canoll, P.D., Barnea, G., Levy, J.B., Sap, J., Ehrlich, M., Silvennoinen, O., Schlessinger, J. and Musacchio, J.M. The expression of a novel receptor-type tyrosine phosphatase suggests a role in morphogenesis and plasticity of the nervous system. Brain Research Developmental Brain Research, 1993, 75:293-298.
b. Canoll, P.D., Petanceska, S., Schlessinger, J. and Musacchio, J.M. Three forms of RPTP-b are differentially expressed during gliogenesis in the developing rat brain and during glial cell differentiation in culture. Journal of Neuroscience Research, 1996, 44:199-215.
c. Canoll, P.D., Musacchio, J.M., Hardy, R., Reynolds, R., Marchionni, M.A. and Salzer, J.L. GGF/Neuregulin promotes the proliferation and survival and inhibits the differentiation of cells in the oligodendrocyte lineage. Neuron, 1996, 17: 229-243.
d. Canoll, P.D., Kraemer, R., Teng, K.K., Marchionni, M.A., Salzer, J.L. GGF/Neuregulin induces a phenotypic reversion of differentiated oligodendrocytes. Molecular Cellular Neuroscience, 1999, 13: 79-94.
2. Adult Glial Progenitors As The Cell Of Origin For Proneural Glioma: My research over the last 10 years has focused on understanding the cellular and molecular mechanisms of glial transformation and gliomagenesis. Using stereotaxic delivery of transforming retroviruses, my laboratory was the first to show that OPCs in the adult what matter that can give rise to malignant gliomas. We have also developed several genetically engineered mouse models to determine the effects of specific genetic alterations on adult glial progenitors and to characterize how these alterations lead to tumor formation. Using cross-species comparison of genomic and transcriptomic analyses we discovered that these mouse models resemble a specific subtype of human glioma (Proneural GBM). We also identified the master regulator transcription factors that control the Proneural phenotype and characterized how this transcriptional network changes during glial transformation and glioma progression. In collaboration with Patrizia Casaccia (Mount Sinai Medical School) we have shown how the regulation of OPC proliferation and differentiation is altered during glial transformation. This work has revealed several potential therapeutic targets, such as Topoisomerase IIA, which appear to be particularly important for the treatment of proneural GBM.
a. Assanah M, Lockhead R, Ogden A, Bruce J, Goldman J, Canoll P. Glial progenitors in adult white matter are driven to form malignant gliomas by PDGF expressing retroviruses The Journal of Neuroscience, 2006, 26 (25) 6781-6790.
b. Lei L, Sonabend AM, Guarnieri P, Soderquist C, Ludwig T, Rosenfeld, S, Bruce J, Canoll P, Glioblastoma models reveal the connection between adult glial progenitors and the Proneural phenotype. PLOS ONE, 2011.
c. Sonabend AM, Bansal M, Guarnieri P, Lei L, Amendolara B, Soderquist C, Leung R, Yun J, Sisti J, Kennedy B, Bruce S, Bruce, R, Shakya R, Ludwig T, Rosenfeld SS, Sims PA, S, Bruce JN, Califano A, Canoll P, The Transcriptional Regulatory Network of Proneural Glioma Determines the Genetic Alterations Selected During Tumor Progression. Cancer Research, 2014, 74(5), 1440-1451. doi: 10.1158/0008-5472.CAN-13-2150
d. Magri, L, Swiss, VA, Jablonska, B, Lei, L, Pedre, X, Walsh, M, Zhang, W, Gallo, V, Canoll, P, Casaccia, P E2F1 Coregulates Cell Cycle Genes and Chromatin Components during the Transition of Oligodendrocyte Progenitors from Proliferation to Differentiation, The Journal of Neuroscience, 2014, 22 January 34(4): 1481-1493
3. Preclinical Models To Test The Effects Of Targeted Therapy In Glioma: During the course our mechanistic studies on gliomagenesis, my lab has developed several new rodent glioma models, including a variety of mouse models that harbor different genetic alterations and fluorescent/bioluminescent