Abstract IA-002: Microenvironmental regulation of glioblastoma radioresistance

Abstract

Abstract Glioblastomas (GBM) have long been recognized as radioresistant tumors. Defining the mechanisms mediating their radioresistance should provide a rational basis for designing target-based strategies that enhance GBM radiosensitivity. Towards this end, a major barrier is the availability of an experimental model system that replicates the molecules and processes that determine GBM radioresponse. Laboratory studies have suggested that the brain microenvironment plays a role in GBM radioresistance. Moreover, it is well established that GBMs comprise a diverse set of tumors that are highly variable in terms of histology, mutations, and gene expression profiles. Yet, despite this extensive biological heterogeneity, although some GBMs respond better than others, they all essentially fail radiotherapy. This relatively "homogeneous" clinical response in a background of inter-tumor heterogeneity further suggests that the microenvironment plays a significant role in determining GBM radioresponse. Complicating this proposed role for the microenvironment, however, is that the brain is comprised of structurally and functionally diverse microenvironments; whether each contributes in a similar manner to GBM radioresistance is unclear. To investigate the role of specific brain microenvironments in determining tumor cell radioresponse, we used orthotopic xenografts initiated from GBM stem-like cells (GSCs) as a model system. After implantation of GSCs into the right striatum of nude mice, tumor cells were detectable throughout the striatum, the corpus callosum and the olfactory bulb. To measure radiosensitivity, the proliferation status of individual tumor cells was defined according to the incorporation of 5-chloro-2'-deoxyuridine (CldU), which was delivered at 4-20 days after brain irradiation. After an initial loss of proliferating tumor cells in the corpus callosum and striatum after irradiation, there was only a minor recovery. In contrast, the proliferation of tumor cells located in the olfactory bulb began to recover at 4 days and returned to unirradiated levels by day 12 post-irradiation. These results suggest that tumor cells in olfactory bulb are relatively radioresistant. Using ddPCR to define the percent human cells in the right hemisphere and the olfactory bulb as a function of time after irradiation also suggested that the tumor cells in the olfactory bulb were relatively radioresistant. RNAseq analysis showed that the gene expression profile for NSC11 tumor cells in the olfactory bulb as compared to those growing in the right hemisphere included signaling pathways and processes associated with radioresistance. Overall, these results indicate that the murine olfactory bulb, which is highly enriched in neurons and interneurons, provides a radioprotective niche for tumor cells. In addition, these data suggest that human tumor cells grown in the murine olfactory bulb may provide an experimental model that simulates GBM radioresistance. Citation Format: Philip Tofilon. Microenvironmental regulation of glioblastoma radioresistance [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr IA-002.