Projects
CXCR4 signaling in brain tumors
We determined that CXCR4 signaling is dysregulated in brain tumor cells as compared to normal counterparts resulting in abnormally prolonged suppression of cAMP in response to CXCL12. These low levels of cAMP stimulate brain tumor growth and appear to comprise a mechanism of resistance to anti-tumor therapy. Such sustained suppression of cAMP suggests that normal counter-regulation of CXCR4 signaling, known as desensitization, is not occurring in brain tumor cells. Desensitization involves the phosphorylation of ligand-bound CXCR4 by kinases belonging to the G-protein receptor kinase (GRK) family and the binding of arrestins. We are currently examining how changes in expression and activation of GRKs and changes in CXCR4 phosphorylation regulate cAMP suppression and CXCL12-induced tumor cell growth in vitro and in vivo.
CXCR4 signaling in cerebellar development
CXCR4 activation is essential for normal cerebellar development. We showed that CXCL12 works in concert with sonic hedgehog to regulate cerebellar granule neuron proliferation. We are currently examining sonic hedgehog modulation of CXCR4 signaling, especially CXCR4 desensitization and CXCR4-mediated cAMP suppression.
Phosphodiesterase 4 in brain tumor formation and growth
We demonstrated that phosphodiesterases type 4 is a potent stimulator of brain tumor growth in vivo and that inhibition of PDE4 has significant anti-brain tumor growth effects. We are currently investigating whether PDE4A can contribute to oncogenesis and by which mechanism it promotes growth.
Generation of primary intracranial xenograft models of pediatric brain tumors
In collaboration with Dr. Jeffrey Leonard from the Department of Neurosurgery we have established primary intracranial xenografts of human brain tumors. These in vivo cultures provide a novel model system in which to study the biology of human brain tumors.