Merlin regulation of glial cell growth and motility

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DESCRIPTION (provided by applicant): Brain tumors represent a significant source of morbidity and mortality in both children and adults. While brain tumors are less common than other forms of cancer, the mean survival of patients with malignant brain tumor is less than one year. This dismal success rate in treating patients with brain tumors reflects a rudimentary understanding of the key genetic and molecular changes important for brain tumor formation and malignant progression. Our ability to design better therapies for these devastating cancers is heavily dependent on the identification of the critical molecular changes that drive tumor formation and progression. Individuals with the inherited tumor predisposition syndrome, neurofibromatosis type 2 (NF2), develop ependymomas and spinal astrocytomas. Both ependymomas and astrocytomas are glial cell malignancies (gliomas) that arise from neoplastic glial cells. Studies from several laboratories, including our own, have shown that NF2 gene inactivation and loss of expression of the NF2 gene product, merlin or schwannomin, represents the most common genetic change in ependymoma, both in individuals with NF2 as well as in individuals with sporadic ependymoma. My preliminary studies, using Nf2-deficient glial cells, have demonstrated that merlin regulates growth and motility in astrocytes. Nf2-deficient astrocytes show increased activation of Src and its downstream effectors FAK and paxillin, all previously shown to be involved in the regulation of cell growth and motility. In addition, I showed that merlin regulation of growth and motility in Nf2-deficient glial cells is Src-dependent. In this proposal, I plan to test the hypothesis that merlin functions to control cell growth and motility in glia by regulating Src activity. Specifically, I will (1) determine how merlin regulates Src oncoprotein activity and (2) determine how merlin-dependent Src regulation controls glial cell growth and motility. These studies are focused on defining the mechanism underlying merlin growth regulation in the nervous system relevant to identifying targets for future therapeutic anti-cancer drug design. Collectively, these experiments are directed towards elucidating one of the key growth control pathways de-regulated in brain tumors. These experiments will be critical for the identification of potential targets for therapeutic drug design aimed at ameliorating one of the growth control defects in brain tumors, which may lead to improved treatments for these deadly human cancers.