CSIG-39. Fyn, AN ONCOGENE THAT REDUCES GLIOBLASTOMA SURVIVAL YET SENSITIZES TO CHEMO-RADIOTHERAPY

Abstract

Fyn, a Src family kinase member (SFK), has oncogenic activities. However, the function of Fyn in malignant brain tumors (GBM) remains contradictory. Bioinformatics network analysis of the transcriptome of GBM neurospheres suggested that Fyn is a highly connected node. Thus, Fyn was selected as a potential regulator of glioma behavior. We investigated the role of Fyn using in vitro and in vivo models. Fyn expression correlates positively with GBM cell aggressiveness. The analysis of the effects of Fyn knockdown in NP mouse glioma neurospheres showed that cell proliferation and migration was decreased compared to NP-control cells. Using an intracranial glioma model, we found that Fyn-knockdown glioma neurospheres displayed reduced tumor growth and prolonged survival compared with NP tumors. We also developed a stringent Fyn-deficient genetic model using the Sleeping Beauty transposase system. The tumors were induced by injecting plasmids encoding: N-Ras/shp53 (NP) or N-Ras/shp53/shFyn (NPF) into the neonatal periventricular region. Fyn knockdown (NPF) increased animal survival. The histopathological evaluation of gliomas indicates that loss of Fyn reduced malignant features such as pseudopalisades, necrosis, hyper vascularization and oncostreams. Nevertheless, the survival analysis of TCGA treated patient data indicates that GBM with lower levels of Fyn had reduced survival. Therefore, we evaluated the effects of therapies on Fyn knockdown cells. The analysis surprisingly showed that NPF neurospheres were more resistant to treatment than NP. Fyn loss decreases glioma aggressiveness but induces less response to therapies. These results indicate an important role for Fyn modulating many glioma cellular processes and its relevance as a novel regulator of GBM behavior and therapy response.