MPTH-08ZEB1 IS UBIQUITOUSLY EXPRESSED ACROSS SUBTYPES IN HUMAN GLIOBLASTOMA AND A SURROGATE MARKER OF TUMOR PURITY

Abstract

OBJECTIVE: The transcription factor ZEB1 has gained attention in tumor biology of epithelial cancers because of its suggested roles in epithelial-mesenchymal transition, DNA repair, mediation of stem cell properties and tumor-induced immunosuppression, but its role in CNS tumors, especially glioblastoma multiforme is not well understood. METHODS: We comprehensively characterized ZEB1 expression at single cell level by automated classification of 1.6 million nuclei in biopsy samples from 273 human astroglial tumors and correlated its expression with EGFR status, IDH1 mutation and Ki67, CD44, GFAP and CD68 immunohistochemistry. Interaction of ZEB1 and EGFR signalling was interrogated in vitro by realtime quantitative PCR and immunocytochemistry in glioma stem cell lines from subtype-stratified parental tumors based on RNAseq transcriptomic gene expression profiles. RESULTS: ZEB1 is expressed in nearly all examined tumors but in highly variable fraction of cells. Co-staining of reactive CNS cell types in non-tumor tissue show that besides bona fide tumor cells, only reactive astrocytes but not leucocytes, microglia and macrophages contribute to the ZEB1 positive population. In GBM, ZEB1 labelling index correlates with EGFR amplification and IDH1 mutation, but EGFR modulation by cetuximab treatment did not alter ZEB1 expression in vitro. CONCLUSION: ZEB1 is expressed ubiquitously and across molecularily defined subtypes in glioblastoma multiforme as well as in non-GBM astroglial tumors. ZEB1 labelling varies across GBM subtypes, but a causal link remains questionable. We speculate that ZEB1 is a pan-astroglial tumor marker that reflects tumor purity.