The identification of a stem cell regulatory gene which is aberrantly expressed in glioma and associated with patient survival would increase the understanding of the role of glioma cancer stem cells (GCSCs) in the virulence of gliomas. Interrogating the genomes of over 4000 brain cancers we identified ZEB1 deletion in ~15% (grade II and III) and 50% of glioblastomas. Meta-analysis of ZEB1 copy number status in 2,988 cases of glioma revealed disruptive ZEB1 deletions associated with decreased survival. We identified ZEB1 binding sites within the LIF (stemness factor) promoter region, and demonstrate LIF repression by ZEB1. ZEB1 knockdown in GCSCs caused LIF induction commensurate with GCSC self-renewal and inhibition of differentiation. IFN-γ treatment to GCSCs induced ZEB1 expression, attenuating LIF activities. These findings implicate ZEB1 as a stem cell regulator in glioma which when deleted leads to increased stemness, tumorigenicity and shortened patient survival.

Objective: To address the unmet medical need to better prognosticate patients with diffuse gliomas and to predict responses to chemotherapy regimens.Methods: ZEB1 alterations were retrospectively identified from a cohort of 1,160 diffuse glioma patients. Epigenome-wide association scans (EWAS) were performed on available data. We determined the utility of ZEB1 as a prognostic indicator of patient survival in diffuse gliomas and assessed the value of ZEB1 to predict the efficacy of treating diffuse glioma patients with procarbazine, CCNU, and vincristine along with radiation at diagnosis. Decision curve analysis (DCA) was used to determine if ZEB1 added benefit to clinical decision-making over and above conventional methods.Results: Fifteen percent of diffuse glioma patients had a ZEB1 deletion. ZEB1 deletion was associated with poor overall survival (OS) with and without adjustment for age and tumor grade (adjusted HR: 4.25; 95% CI: 2.35 to 7.66; P < 0.001). Decision curve analysis confirmed that ZEB1 status with or without IDH1 was more beneficial to clinical decision making than conventional information such as age and tumor grade. We showed that ZEB1 regulates TERT expression, and patients with ZEB1 deletions likely subsume patients with mutant TERT expression in diffuse gliomas. ZEB1 influenced clinical decision making to initiate procarbazine, CCNU, and vincristine treatment.Conclusion: We demonstrate the prognostic value of ZEB1 in diffuse glioma patients. We further determine ZEB1 to be a vital and influential molecular marker in clinical decisions that exceed conventional methods regarding whether to treat or not treat patients with diffuse glioma.

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For decades human brain tumors have confounded our efforts to effectively manage and treat patients. In adults, glioblastoma multiforme is the most common malignant brain tumor with a patient survival of just over 14 months. In children, brain tumors are the leading cause of solid tumor cancer death and gliomas account for one-fifth of all childhood cancers. Despite advances in conventional treatments such as surgical resection, radiotherapy, and systemic chemotherapy, the incidence and mortality rates for gliomas have essentially stayed the same. Furthermore, research efforts into novel therapeutics that initially appeared promising have yet to show a marked benefit. A shocking and somewhat disturbing view is that investigators and clinicians may have been targeting the wrong cells, resulting in the appearance of the removal or eradication of patient gliomas only to have brain cancer recurrence. Here we review research progress in immunotherapy as it pertains to glioma treatment and how it can and is being adapted to target glioma stem cells (GSCs) as a means of dealing with this potential paradigm.

OBJECTIVE Glioblastoma has been known to be resistant to chemotherapy and radiation, whereas the underlying mechanisms of resistance have not been fully elucidated. The authors studied the role of the transcription factor ZEB1 (zinc finger E-box-binding homeobox 1 protein), which is associated with epithelial-mesenchymal transition (EMT) and is central to the stemness of glioblastoma, to determine its role in therapeutic resistance to radiation and chemotherapy. The authors previously demonstrated that ZEB1 is deleted in a majority of glioblastomas. METHODS The authors explored resistance to therapy in the context of ZEB1 loss and overexpression in glioma stem cells (GSCs) and in patient data. RESULTS Patients with ZEB1 loss had a shorter survival time than patients with wild-type ZEB1 in both the high- and low-MGMT groups. Consistent with the clinical data, mice implanted with ZEB1 knockdown GSCs showed shortened survival compared with mice inoculated with nonsilencing control (NS) short-hairpin RNA (shRNA) GSC glioblastoma. ZEB1-deleted GSCs demonstrated increased tumorigenicity with regard to proliferation and invasion. Importantly, GSCs that lose ZEB1 expression develop enhanced resistance to chemotherapy, radiotherapy, and combined chemoradiation. ZEB1 loss may lead to increased HER3 expression through the HER3/Akt pathway associated with this chemoresistance. Conversely, overexpression of ZEB1 in GSCs that are ZEB1 null leads to increased sensitivity to chemoradiation. CONCLUSIONS The study results indicate that ZEB1 loss in cancer stem cells confers resistance to chemoradiation and uncovers a potentially targetable cell surface receptor in these resistant cells.