CNSC-40. DECIPHERING CELLULAR TRANSLATION CONTROL IN NEURON-GBM INTERACTIONS

Abstract The intricate relationship between neurons and cancer cells is critical for tumorigenesis and neuronal dysfunction, however underlying mechanisms and potential therapeutic opportunities are not well-established. Neuron-glioblastoma (GBM) interaction has been evaluated at the transcriptomic level; however, mRNA levels poorly represent the proteome. Selective, rapid, and highly precise translation of selected mRNAs is critical for synaptic transmission as well as cancer progression. However, there is a major gap in our understanding of how neuronal signaling regulates the cancer proteome, associated with progression and therapeutic resistance. We established a powerful neuron-human GBM PDX co-culture system, where neurons and GBM cells form synapses and drive neuronal hyperexcitability in vitro, as well as GBM aggressiveness, in vitro and in vivo. We demonstrate that neuronal signaling induced critical signaling pathways in GBM cells that converge on translation control signaling pathways upstream of translation control. Interestingly, neuronal signaling drove selective overexpression and activation of major cap-binding proteins eIF4E and the RNA helicase eIF4A1, the eIF4F translation initiation complex proteins critical in oncogenesis via regulating selective translation of a network of mRNAs. Most importantly, these changes preceded the increase in de novo protein synthesis and proliferation, suggesting that selective mRNA translation controlled by eIF4E and eIF4A1 represents early changes in neuronal signaling-driven GBM progression. We show that paracrine factors released in response to neuron-GBM communication contribute to proliferation and activate signaling that controls selective translation. Lastly, we show that neuronal-signaling-driven GBM aggression was independent of their genomic background. We are performing ribosome profiling and proteomics experiments, which will allow us to decipher the mechanisms of neuronal signaling-driven translational remodeling in GBM cells and dissect synaptic and paracrine signaling as upstream of translation regulation. These experiments will establish the role of translational remodeling control of GBM in response to neuronal signaling and promise to identify novel post-transcriptional vulnerabilities.