NRF1 Transcriptomic Signatures Contribute to the Pathogenesis of the Most Aggressive Brain Cancer - Glioblastoma

Abstract

Glioblastomas (GBMs, grade IV astrocytoma or glioma) are the most aggressive and lethal of all brain cancers. GBM patients have short survival and poor clinical prognosis. Despite decades of research, the standard of care for GBM treatment has not changed significantly. The lack of curative treatment modalities for patients with this type of brain tumor highlights the importance of research that helps to discover novel therapeutic targets. Nuclear respiratory factor 1 (NRF1) transcription factor (TF) has been reported to be one of the top active TFs in human cancer, but its role in GBM remains unknown. This thesis research focuses on transcriptomic signatures modified by NRF1 that influence gender specific GBM heterogeneity, acquisition of different GBM stem cells, and resistance to therapy. NRF1 activity by transcription factor target enrichment analysis, causal NRF1 target gene signatures by Bayesian Network Inference with Java Objects (BANJO), and Markov Chain Monte Carlo (MCMC)-based gene order were examined in four independent GBM cohorts to identify drivers of GBMs as well as prognostic indicators of poor response to radiation and chemotherapy. Initial discovery showed that NRF1 has higher mRNA expression and transcription factor activity in GBMs compared to non-tumor brain tissue. NRF1 activity was associated with transcriptomic signatures of neurogenesis, cell stemness, epithelial-mesenchymal transition, and cell cycle progression. Poor survival outcomes and resistance to Temozolomide therapy were associated with higher NRF1 expression including its targets. However, these findings did not reveal the impact of molecular heterogeneity and gender on aggressiveness of GBMs. Therefore, the gender specific NRF1 transcriptomic landscape was analyzed GBM patients, and herein we report sex-specific differences in causal interaction of NRF1 target genes with GBM or NRF1. Risk estimates for GBM were increased by greater than 100-fold with the joint effect of NRF1-driven gene signatures - CDK4, DUSP6, MSH2, NRF1, and PARK7 in female GBM patients and CDK4, CASP2, H6PD, and NRF1 in male GBM patients. High NRF1 activity driven causal gene networks predict poor survival and resistance to chemoradiation therapy in IDH1 wild-type mesenchymal GBM patients. NRF1-regulatable miRNAs were also associated with poor response to therapy in IDH1 wild-type mesenchymal GBM. In contrast to higher NRF1 activity in glioma tumors, lower NRF1 activity was observed in human neurodegenerative disease samples and the loss of NRF1 activity was associated with the neurodegeneration-related gene signatures. In summary, novel discoveries of this thesis research show that aberrant NRF1 activity contributes to the pathogenesis and severity of GBM; molecularly distinct GBM subtypes (mainly mesenchymal) that contribute to cancer recurrence are the result of dysregulation of NRF1 driven causal genes and miRNAs involved in cancer cell stemness and epithelial-to-mesenchymal transition. Further analyses of NRF1 gene signatures will pave the way for next generation targeted therapies and drug combination strategies for GBM patients.