PATH-17. Spatial Transcriptomics Uncovers the Functional Role of SLC6A6 in Cellular Senescence and Its Pathological Significance in Glioblastoma

Abstract Malignant glioblastoma exhibits cellular senescence characterized by changing tumor microenvironment. Solute carrier family 6 member 6 (SLC6A6), a multichannel transmembrane protein, plays a crucial role in in regulating cell proliferation, apoptosis, differentiation, and cellular osmolality. However, the molecular mechanism of SLC6A6 in the pathogenesis of glioblastoma remains unknown. We explored the architecture complexity of GBM through spatial transcriptomics and we found that SLC6A6 emerged as a particularly important gene of interest. We examined expression profiling of SLC6A6 in tumor samples derived from 50 patients with glioblastoma, and evaluated associations between SLC6A6 expression levels and survival outcome using Kaplan–Meier survival and Cox regression analyses. We applied short hairpin RNA (shRNA) and overexpression (OE) vectors to construct SLC6A6-knockdown (KD) and -OE glioblastoma cell lines, respectively. We established an orthotopic mouse model of glioblastoma. Clinically, patients with high expression of SLC6A6 had a worse prognosis (reduced overall survival [OS]). Downregulation of SLC6A6 protein inhibited malignant phenotypes of glioblastoma cells in vitro. SLC6A6 affected tumor senescence by directly binding to CSK with its N-terminal cytoplasmic domain, thereby enhancing AKT phosphorylation. Furthermore, SLC6A6 KD inhibited tumor growth and extended survival in a xenograft mouse model. Collectively, SLC6A6 can promote malignant progression and inhibit cellular senescence of glioblastoma by affecting the CSK/AKT/FOXO1 signaling pathway. Therefore, SLC6A6 might be a valuable target for therapy of glioblastoma.