Diffusely infiltrating gliomas are the most common type of primary brain tumor seen in adults. Patients with low grade glioma (LGG) can survive for many years, but often suffer from seizures and cognitive impairment, and these symptoms are associated with an unfavorable prognosis. Glioma cells diffusely infiltrate cortical tissue, where tumor cells aggregate around neuronal cell bodies, a growth pattern referred to as perineuronal satellitosis, however the effects of tumor cells on neurons has not been well defined. To address this important issue we generated a mouse model that recapitulates the genetic and histological features of diffusely infiltrating LGG. In our model tumor growth is driven by PDGFA overexpression and p53 deletion in a RiboTag-Camk2a-Cre transgenic mouse. The RiboTag system allows for the isolation and sequencing of ribosome-bound transcripts from Camk2a neurons to obtain a measure of transcription and translation. Our analysis in non-tumor bearing brains identified neuron-specific genes that are highly regulated at the level of translation. mTOR signaling regulates cell growth, proliferation, and translation in response to diverse stimuli. To characterize mTOR signaling in our model we used immunohistochemical staining of pS6 as a marker of mTOR activity and found that neurons within the glioma infiltrated cortex have lower levels of pS6 staining compared to neurons in the surrounding cortex. To further assess these results we are using the RiboTag system to identify alterations in neuronal transcription and translation that occur in our model during glioma formation and in response to mTOR targeted treatments. These studies will provide new insights into the neuronal alterations contributing to seizures and cognitive impairment in glioma and enable the identification of potential molecular targets for novel therapies to treat the devastating consequences of cortical dysfunctions associated with glioma.
Citation Format: Daniela Torres, Angeliki Mela, Sohani Das Sharma, Nicholas Hornstein, Peter Sims, Peter Canoll. Characterization of neuronal alterations in a new mouse model of low grade glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1841. doi:10.1158/1538-7445.AM2017-1841