Cancers of the spinal cord are uncommon neoplasms, the majority of which are glial cell tumors (ependymoma and astrocytoma) thought to arise from multipotent neuroglial progenitor (stem) cells. Whereas many spinal ependymomas exhibit indolent behavior, the only treatment option for clinically symptomatic tumors is surgery. In this regard, medical therapies are unfortunately lacking due to an incomplete understanding of the critical growth control pathways that govern the function of spinal cord (SC) neural stem cells (NSCs). To define the key intracellular signaling pathways that control SC progenitor function relevant to SC gliomagenesis, our laboratory has focused on the neurofibromatosis type 2 (NF2) inherited cancer syndrome, a disorder in which affected individuals are predisposed to SC glial malignancies. The importance of the NF2 gene in SC glioma formation is further underscored by the observation that NF2 gene inactivation predominates in sporadic ependymomas of the spinal cord. In this proposal, I plan to employ NF2 as a genetic model system to define the molecular mechanism(s) underlying normal NSC growth and differentiation regulation specifically in the spinal cord. The overall objective of this proposal is to elucidate he mechanism(s) underlying the molecular and cellular heterogeneity in distinct CNS stem cell population as an initial step towards developing targeted therapies for clinically-progressive spinal cord ependymomas. I hypothesize that merlin negatively regulates NSC proliferation and glial differentiation in a region-specific manner by suppressing ErbB2/JNK activation.
In Specific Aim 1, I propose to determine how merlin regulates spinal cord NSC growth and differentiation in vitro and in vivo using a combination of primary neurosphere cultures in vitro and Nf2 conditional knockout (CKO) mice in vivo.
In Specific Aim 2, I propose to determine how merlin regulates NSC function in a CNS region specific manner using neurosphere cultures from the brainstem and forebrain. A combination of isoform-specific reagents and Nf2 CKO mouse strains, shRNA (genetic) and pharmacologic inhibitors, and constitutively-activated receptor tyrosine kinases will be employed. Collectively, these studies provide unprecedented opportunities to leverage developmental neurobiology to identify new drug targets for the treatment of these CNS cancers.
The vast majority of SC tumors are ependymomas (glial cell tumors) that originate from progenitor/stem cells in the developing spinal cord. Although ependymomas from different regions of the CNS are histologically similar, they are clinically and genetically distinct, suggesting that they represent a collection of different diseases with unique genetic drivers and responses to therapy. I plan to employ NF2 as a genetic model system to define the molecular mechanism(s) underlying normal NSC growth and glial differentiation in a CNS region-specific dependent manner.
|Garcia, Cynthia; Gutmann, David H (2014) Nf2/Merlin controls spinal cord neural progenitor function in a Rac1/ErbB2-dependent manner. PLoS One 9:e97320|