Details

Autor(en) / Beteiligte

• Kim, Leo
• Jin, Xun
• Sanvoranart, Tanwarat
• Wallace, Lisa C
• Rich, Jeremy

Titel

STEM-15. IDENTIFYING NICHE-INDEPENDENT PRO-TUMORIGENIC FACTORS IN GLIOBLASTOMA

Ist Teil von

• Neuro-oncology (Charlottesville, Va.), 2017-11, Vol.19 (suppl_6), p.vi229-vi229

Ort / Verlag

US: Oxford University Press

Erscheinungsjahr

2017

Quelle

Oxford Journals 2020 Medicine

Beschreibungen/Notizen

• Glioblastoma (GBM) is the most prevalent malignant primary brain tumor with conventional therapy offering only palliation. Despite extensive genomic and epigenetic studies, clinical breakthroughs in GBM remain elusive, in part, due to intratumoral heterogeneity. To overcome differential expression of diverse oncogenic drivers in tumor microenvironments, we interrogated the Ivy Glioblastoma Atlas Project dataset — an RNA-seq database of GBM specimens microdissected based on pathognomonic histological features — to identify niche-independent pro-tumorigenic factors that may be targeted to improve clinical outcomes. Based on this analysis and cross-referencing TCGA GBM RNA-seq and clinical data, 46 genes were identified as differentially expressed in GBM compared with non-tumor tissue and predicted significantly worse clinical outcomes. Through multivariate analysis adjusted for age, treatment regimen, and gene expression level, the gene Tapasin-binding protein-like (TAPBPL) was identified as an independent negative predictor of GBM patient survival. Interrogation of patient tissues and glioma stem cells (GSCs) revealed elevated TAPBPL expression in primary GBM tissues relative to non-tumor brain tissues and in GSCs compared with neural progenitor cells (NPCs). We further investigated the functional role of TAPBPL the GBM hierarchy through CRISPRi- and shRNA-mediated knockdown in our panel of patient-derived GSCs. Depleting TAPBPL attenuated self-renewal and viability of both proneural and mesenchymal GSCs. To infer TAPBPL-associated biological programs in GBM, we examined gene signatures positively and negatively correlated with TAPBPL expression or TAPBPL-correlated genes. In addition to antigen presentation, TAPBPL expression was most positively correlated with interferon responses and apoptosis signatures. As predicted by promoter and enhancer analysis, TAPBPL expression is modulated by IRF1, concordantly increased by exogenous treatment with IFN-γ in a dose-dependent manner. Collectively, our results suggest that TAPBPL promotes GBM progression and GSC maintenance across all tumor microenvironments.