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Scott L. Pomeroy, M.D., Ph.D.

Associate Professor of Neurology
Chairman, Department of Neurology at the Children's Hospital

Children's Hospital
Neurology, Fegan 11
300 Longwood Ave
Boston, MA 02115
Telephone: 617 355-6874
Fax: 617-730-0286
Email: scott.pomeroy@childrens.harvard.edu
Predocs: 1 Postdocs: 3 Completed PhD's: 0

 Scottt Pomeroy

Medulloblastomas are the most common malignant brain tumors of childhood, with 40-50% overall mortality. We used microarray expression profiling to demonstrate that medulloblastomas arise from cerebellar granule cells and are molecularly distinct from supratentorial PNETs, resolving a decades-long dispute on the origin of medulloblastomas (Pomeroy et al., Nature 2002; 415:436-442). To address whether genes that regulate granule cell development also regulate medulloblastoma growth, we assayed the neurotrophin receptors TrkB and TrkC, which are differentially expressed as granule cells progress to their terminally differentiated state in the Internal Granule Cell Layer (Segal et al., J. Neurosci. 1995; 15:4970-498). The neurotrophin-3 receptor, TrkC, was found to be highly expressed in medulloblastomas with favorable prognosis, serving as an independent marker of clinical outcome (Segal et al., Proc Natl Acad Sci USA 1994; 91:12867-71). Moreover, we discovered that TrkC, which normally promotes granule cell survival, induced apoptosis of medulloblastomas in vitro and slowed the growth of medulloblastoma xenografts (Kim et al., Cancer Research 1999; 59:711-719). Apoptosis was induced through signaling cascades normally activated by Trk receptor tyrosine kinases, including phosphoinositol 3-kinase/p70S6Rsk and three parallel signaling cascades: ERK (p44/p42), JNK/SAPK, and p38MAPK. Activation of ERK5 and MEF2 appear to be both necessary and sufficient for neurotrophin-induced apoptosis (Sturla et al., Cancer Research 2005; 65:5683-5689).

We are using the Ptc +/- mouse model of medulloblastoma to test developmental mechanisms identified by expression profiling. Tumors arise in Ptc +/- heterozygous mice through a multistep process, starting with persistent proliferation of progenitors followed by emergence of neoplastic cells (Kim et al., Develop. Biol. 2003; 263:50-66). We now are testing whether Wnt collaborates with Shh/PTCH to promote this pattern of growth.

 

References:

  • Kim JYH, Sutton ME, Lu DJ, Goumnerova LC, Goritchenko L, Cho TA, Lam KK, Billet AL, Tarbell NJ, Allen JA, Wu J, Stiles CD, Segal RA, Pomeroy SL. Activation of the neurotrophin-3 receptor TrkC induces apoptosis of medulloblastomas. Cancer Research 1999; 59:711-719.
  • Pomeroy SL, Tamayo P, Gaasenbeek M, et al. Prediction of central nervous system embryonal tumour outcome based on gene expression. Nature 2002; 415:436-442.
  • Kim JYH, Nelson AL, Algon SA, Graves O, Sturla LM, Goumnerova LC, Rowitch DH, Segal RA, Pomeroy SL. Medulloblastoma tumorigenesis diverges from cerebellar granule cell differentiation in patched heterozygous mice. Dev. Biol. 2003; 263:50-66.
  • Kho AT, Zhao Q, Cai K, Butte A, Kim JYH, Pomeroy SL, Rowitch DH and Kohane IS. Conserved mechanisms across development and tumorigenesis revealed by a mouse development perspective of human cancers. Genes Dev. 2004;18:629-40.
  • Sturla LM, Cowan CW, Guenther L, Castellino RC, Kim JYH, Pomeroy SL. A novel role for extracellular signal-regulated kinase 5 and myocyte enhancer factor 2 in medulloblastoma cell death. Cancer Research 2005; 65:5683-5689.