Abstract
BACKGROUND: Metabolic reprogramming in glioblastoma (GBM) is a putative determinant of GBM subtype, malignant cell state, and tumor-immune crosstalk. In the present study, we investigated how polyamine metabolic rewiring contributes to the malignant cell-intrinsic and microenvironment-dependent biological processes underpinning GBM subtype classification. METHODS: Liquid chromatography/tandem mass spectrometry was used for polyamine quantification in human and murine GBM tumors and cell lines. Through single-cell RNA sequencing, metabolic profiling, and additional functional experiments, we dissect the malignant cell-intrinsic and paracrine signaling processes regulated by SAT1 (spermidine/spermine-N1-acetyltransferase1) and its product, N1-acetylspermidine. RESULTS: We find that polyamine acetylation is elevated in human and murine GBM tumors and contributes to the classification of mesenchymal/plurimetabolic GBM through both regulation of tumor-cell intrinsic glucose metabolism and by facilitating metabolic crosstalk with tumor-associated macrophages/myeloid cells (TAMs). The impact of SAT1 on tumor cell metabolism is mediated, at least in part, by N1-acetylspermdine, the sole polyamine elevated in human and murine tumors. Furthermore, the relatively high levels of N1-acetylspermidine released by GBM are taken up by myeloid cells to promote intracellular polyamine flux, cellular respiration, and migration. In vivo, both genetic disruption of polyamine acetylation and pharmacological inhibition of polyamine transport reduced myeloid cell infiltration and sensitized tumors to chemoradiation. CONCLUSIONS: Collectively, the findings highlight a previously unidentified role for SAT1 and its product, N1-acetylspermidine, in bridging the metabolic activity of tumor cells and TAMs, together promoting mesenchymal/plurimetabolic states and therapeutic resistance in GBM.