EPCO-22. SINGLE CELL ANALYSIS TO UNDERSTAND SEX DIFFERENCES IN GBM OUTCOME

Abstract

Abstract Males have a higher incidence and mortality in certain cancers compared to females. The same is true in glioblastoma (GBM) regardless of age, suggesting that cell-intrinsic factors rather than extrinsic factors such as circulating sex hormones are causing these sex differences. Our lab has demonstrated cell-intrinsic sex differences with respect to growth, clonogenicity, and in vivo tumorigenesis using an isogenic murine astrocyte cell culture model of GBM (Nf1 -/-; DNp53). Male astrocytes are more likely to adapt and grow when exposed to irradiation-induced stress compared to female astrocytes, which are more likely to undergo growth arrest after the same exposures. These sex differences in response to treatment can be explained by the different chromatin and transcriptional profiles established from the moment of fertilization that can result in different levels of transcriptional heterogeneity, a well-established cause for resistance to induced stress in GBM. However, so far sex has not been considered when exploring transcriptional heterogeneity. As such, we used 10x Genomics technology to extract single nuclei RNA (snRNA) and ATAC (snATAC) sequencing from the same nuclei and identified different levels of transcriptional heterogeneity in male and female astrocytes cells from our model. We also identified different chromatin profiles of crucial genes, such as Sox2, an important TF for the reprogramming of differentiated GBM into stem-like cells, which can then form tumors in vivo. We expect for the male astrocytes to be more effective in escaping growth arrest and adapting to irradiation-induced stress because of these different transcriptional and chromatin profiles. Our work will identify epigenetic mechanisms by which male cells are more able to adapt to treatment-induced stress compared to female cells and will further advance our understanding of sex differences in treatment-response in GBM and cancer overall, while giving avenues for the development of novel treatments.