CSIG-17. CHARACTERIZATION OF AN ALTERNATIVELY SPLICED NTRK2 VARIANT IN GLIOMA: EMPLOYING NOVEL REAGENTS TO UNCOVER NOVEL FUNCTIONS. (5th November 2018)

• Record Type: Journal Article
• Authors: Pattwell, Siobhan; Arora, Sonali; Cimino, Patrick; Ozawa, Tatsuya; Hoffstrom, Benjamin; Boiani, Norman; Bolouri, Hamid; Loeb, Keith; Correnti, Colin; Silber, John; Holland, Eric
• Is Part Of: Neuro-oncology. Volume 20(2018)Supplement 6
• Page Start: vi46
• Page End: vi46
• Publication Date: 2018-11-05
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noy148.183
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Most known for their essential roles in the development and maintenance of the nervous system, the neurotrophins consist of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), NT-3, NT-4 and their respective tropomyosin receptor kinases (TRKs) TrkA, TrkB, and TrkC along with the low affinity nerve growth factor receptor, p75. In addition to known roles in neuronal survival, proliferation, differentiation, and apoptosis, TRKs exert diverse effects on cellular outcomes through their interactions with downstream signaling cascades. Prior to TRKs' established roles in neurobiology, oncogenic TRK was discovered as tropomysoin 3 (TPM3)-TrkA fusion and as a result, oncological studies of the neurotrophin family have identified additional TRK fusions. Putative oncogenic TRK fusions have been observed in various cancer types, but their clinical significance remains unclear and these fusions tend to occur at very low frequencies below 1–2%. The low incidence of these fusions combined with significant overexpression of various TRKs in a multitude of cancers raises the possibility that another aspect of TRK biology, in addition to kinase-domain fusions, may be relevant. Basic scientific and clinical investigation surrounding TRKs' role in cancer has often been hindered due to the nonspecific nature of antibodies and kinase inhibitors, combined with a lack of precise exon-specific expression data from patient populations. Tropomyosin receptor B (TrkB), encoded by the NTRK2 gene, exhibits complex alternative splicing patterns. Here we show a novel role for a TrkB splice variant in gliomas via NTRK2 transcript analyses and immunostaining using a novel antibody engineered specifically to this variant. This NTRK2 splice variant enhances PDGF-driven gliomas in vivo and augments PDGF-induced signaling in vitro . Through the lens of NTRK2, these results highlight the importance of expanding upon whole gene-level and kinase-fusion analyses to explore TRK splicing in basic and translational research.