Known for their essential roles in the development and maintenance of the nervous system, the interactions between neurotrophin receptors and their respective ligands may harbor key information for understanding oncogenesis. In addition to their roles in neuronal survival, proliferation, differentiation, and apoptosis, neurotrophins exert diverse effects on cellular outcomes within and outside of the nervous system. While it has long been known that splicing choices are vital for proper development of normal neural and non-neural tissue, it is becoming widely accepted that aberrant RNA splicing is common feature across all cancers. From alterations in splicing factors to changes gene expression, the discovery of isoform specific oncogenes has the potential to open new avenues for therapeutic targets. The projects proposed here focusing on an alternatively spliced neurotrophin receptor, TrkB, would be among the first to combine neurotrophin biology and alterative splicing in the context of tumor modeling within and outside the central nervous system (CNS). This grant proposes to determine whether dysregulated expression of an alternatively spliced neurotrophin receptor, TrkB.T1, is necessary and sufficient for tumor formation within and outside the CNS. Preliminary data from The Cancer Genome Atlas and immunohistochemical analysis of patient samples utilizing a novel TrkB.T1-specfic antibody confirms the TrkB.T1 variant to be the predominant form of TrkB expressed in tumors within and outside the CNS. Preliminary data utilizing novel vector based mouse modeling further elucidates TrkB.T1?s role in oncogenesis. This tripartite toolkit consisting of (1) TCGA exon expression data (2) a unique TrkB.T1 isoform-specific reagent and (3) a novel TrkB.T1 RCAS-TVA mouse model provides the essential tools required to further explore the role of this alternatively spliced receptor in cancer biology with the goal of identifying a novel therapeutic target for tumors both within and outside the CNS.
The neurotrophin receptors (TRKs) consist of three tyrosine kinase receptor family members that are involved in development of the central nervous system and other organ sites, and were initially discovered through a gene fusion in colon cancer. Alterations in RNA splicing are being appreciated for their contributions to cancer, and the TRK genes have multiple splice variants. One splice variant of the TrkB receptor (NTRK2 gene), known as TrkB.T1, initially thought to have dominant negative function, is actually the most common variant of TrkB in many cancer types. We have created an antibody specific to this TrkB.T1 variant and have used it to detect protein expression in human gliomas and various tumors within and outside of the CNS. Forced expression of TrkB.T1 in mouse models leads to the formation of gliomas and other tumors, such as rhabdomyosarcomas. This data suggests that RNA splicing choices made for TrkB can contribute to the formation of many cancer types. The goals of this project are to determine if the TrkB.T1 splice variant is necessary and sufficient for tumor formation within and outside the CNS.
| Charles, Nikki A; Holland, Eric C; Gilbertson, Richard et al. (2011) The brain tumor microenvironment. Glia 59:1169-80 |
