Evolution of Oncogenic Signatures within Glioblastoma Along a Spatiotemporal Axis

Overview

Glioblastoma is a malignant brain tumor distinguished by intra-tumoral heterogeneity and inevitable recurrence. Residual tumor-initiating cells in the infiltrated normal brain parenchyma, termed the tumor edge, generate molecularly distinct recurrent lesions, the eventual cause of patient lethality. Proteogenomics and non-negative matrix factorization (NMF) identified significant differentially expressed genes and pathways between the tumor core and edge. Identified genes were then analyzed at both the individual and whole genome levels. The tumor edge was found to be highly related to tumor cell infiltration and response to external stimuli. In turn, the tumor core was correlated with response to hypoxia and metabolic adaptation. Furthermore, transcription factor enrichment analysis revealed the oncogenic transcription factor FOXM1 as a central mediator within the tumor core. FOXM1 has been found to bind the protein-kinase MELK to regulate transcriptional activity of the enzymatic catalytic subunit EZH2, promoting radio-resistance. Individual expression analysis of FOXM1 revealed its upregulation to be associated with worse prognosis and treatment resistance. The expression signatures characteristic of tumor edge and core identified the anti-mitotic drug vinorelbine as a potential candidate for drug repurposing to target the FOXM1-dependent molecular shift between tumor edge and core. Collectively, this systematic comparison of tumor core/edge provides a coherent portrait of the prognostically- significant differences in molecular phenotypes associated with intra-tumoral heterogeneity within GBM tumors. This heterogeneity highlights the importance of robust analysis of the surgical unresectable tumor edge, which is the instigator of lethal GBM recurrence. This study also proposes the clinical application of proteogenomic analyses in precision oncology.