Abstract 2534: Neural control of glioma infiltration

Abstract

Abstract Adult glioblastoma multiforme (GBM) is the most common and deadly form of malignant brain cancer. A broad relationship between tumor progression and neuronal stimulation in the microenvironment is known in peripheral tumors, but only a few interactions between neuronal cues and GBM cells have been characterized. By combining in utero electroporation (IUE) with CRISPR/Cas9 and piggyBac transposase genetics, we have developed an endogenous, immunocompetent, in vivo model with which to study these interactions in a native tumor context. Combining this model with Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) we interrogated tumor-neuron interactions. We assessed molecular and physiological changes in tumors during neural stimulation through tumor development with single cell sequencing and spatial transcriptomics. We examined expression data in populations present under stimulation that did not appear or appeared later in control tumors. These data showed axon guidance genes, a family of genes associated with directed cell motility, were upregulated in these populations. To functionally test these findings, we performed a barcoded screen of axon guidance genes in the IUE model followed by individual confirmation with gain and loss of function of individual genes. We found Sema4F affects infiltration of tumors as well as overall survival. Currently we wish to study the abrogation of this infiltration with Sema4F knockout in the context of DREADD stimulation. Completion of this study will provide new insights into neuronal interactions driving tumor progression in GBM. Citation Format: Emmet J. Huang-Hobbs, Yi-Ting Cheng, Yeungjun Ko, Junsung Woo, Akdes Harmanci, Ganesh Rao, Benjamin Deneen. Neural control of glioma infiltration [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2534.