TMIC-43. BIOLOGICAL AND MOLECULAR CHARACTERIZATION OF NOVEL GLIOBLASTOMA TME SUBTYPES USING TRANSCRIPTOMIC ANALYSIS AND NETWORK MODELLING TO IDENTIFY NOVEL TARGETS OF VULNERABILITY

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Abstract New precision medicine therapies are urgently required for glioblastoma (GBM). Recently, we developed a novel GBM classification system, identifying three patient clusters uniquely characterized by tumor microenvironment (TME) composition: TMELow, TMEMedium, and TMEHigh1. Our objective now is to further investigate these subtypes employing transcriptomic analysis and network modelling approaches to identify novel subtype-specific targets of vulnerability. We analyzed transcriptomic data from >600 GBM samples from publicly available and in-house datasets. All samples underwent TME subtyping. Next, we performed differential gene expression (using DESeq2, edgeR) and pathway analysis (using PROGENy). The ‘TRANSFAC’ tool 2 was used to identify potential transcription factors enriched in each TME subtype. TMELow tumours manifested highly upregulated NLGN3 (P=5.777e-5) and HES5 (P=2.233e-3) expression compared to TMEHigh. Moreover, TMEHigh compared to TMELow tumours were enriched for genes associated with tissue remodelling, and showed elevated MMP7 (P=3.051e-6), CLCL13 (P= 3.843e-4), and CXCL5 expression (P= 1.592e-6). PROGENy analysis suggested that the WNT, TRAIL, and JAK/STAT pathways were significantly enriched in TMEHigh, while the PI3K pathway was significantly upregulated in TMEMedium. Additionally, VEGF pathway activity was significantly upregulated in TMELow. TRANSFAC analysis measured by regulatory score (a measure of a transcription factor effect on gene expression) revealed that in TMELow, key transcription factors includes ETS2, NANOG, and MECP2 (regulatory score: 1.97, 1.45, and 1.4, respectively). In TMEMedium, transcription factors HIF1A, PPARA, and CDX2 were identified (regulatory score: 2.52, 2.08 and 1.96, respectively). In TMEHigh, TRANSFAC indicated activiation of transcription factors SMAD3, ETS2, and NFKB1 regulatory score: 2.56, 2.41, 2.24, respectively). Overall these findings highlight distinct molecular signatures across TME subtypes, and provide a deeper understanding of associated molecular mechanisms. Ongoing work is focused on validating key subtype specific genes and associated pathways using spatial proteomics. Prioritised targets will ultimately be interrogated in vivo, as novel subtype-specific treatments. 1. White et al. Ann Oncol. 2023;34(3):300–314. 2. Matys et al. Nucleic Acids Res. 2003;31.

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