The ZEB1 pathway links glioblastoma initiation, invasion and chemoresistance

Abstract

Glioblastoma remains one of the most lethal types of cancer, and is the most common brain tumour in adults. In particular, tumour recurrence after surgical resection and radiation invariably occurs regardless of aggressive chemotherapy. Here, we provide evidence that the transcription factor ZEB1 (zinc finger E-box binding homeobox 1) exerts simultaneous influence over invasion, chemoresistance and tumourigenesis in glioblastoma. ZEB1 is preferentially expressed in invasive glioblastoma cells, where the ZEB1-miR-200 feedback loop interconnects these processes through the downstream effectors ROBO1, c-MYB and MGMT. Moreover, ZEB1 expression in glioblastoma patients is predictive of shorter survival and poor Temozolomide response. Our findings indicate that this regulator of epithelial-mesenchymal transition orchestrates key features of cancer stem cells in malignant glioma and identify ROBO1, OLIG2, CD133 and MGMT as novel targets of the ZEB1 pathway. Thus, ZEB1 is an important candidate molecule for glioblastoma recurrence, a marker of invasive tumour cells and a potential therapeutic target, along with its downstream effectors.Glioblastoma have a poor prognosis, mainly due to infiltrating and therapy resistant cells leading to cancer recurrence. Here, tumor formation, invasion and resistance are not independent but intertwined processes regulated by the EMT activator ZEB1.

Effective Eradication of Glioblastoma Stem Cells by Local Application of an AC133/CD133-Specific T-cell–Engaging Antibody and CD8 T Cells

“…Using patient-derived CSCs, we and others have shown that only these cells are tumorigenic upon xenotransplantation into immunodeficient mice whereas forced differentiation can completely abrogate their tumorigenicity (3,(5)(6)(7)(8). CSCs have repeatedly been reported to preferentially locate to the invasive tumor front (9)(10)(11). This has also been documented for…”

“…Moreover, we targeted the AC133 epitope, an intensely studied CSC marker expressed on CSCs of many tumor entities, including high-grade gliomas. CSCs appear to be ideal targets particularly for postsurgical treatments because they preferentially locate to the invasive front of highly aggressive tumors, thereby often escaping surgical resection (5,9,10,12). Moreover, they are responsible for tumor recurrences due to their high resistance to genotoxic therapies and their unique ability of tumor initiation (1-3, 5, 32).…”

Molecular Mechanisms of Glioma Cell Motility

“…Interestingly, the role of N-cadherin in glioma is postulated not only to be determined by its expression level but also by its distribution in the cell membrane (180). ZEB-1 knockdown in GBM cells showed a loss of invasiveness and concentration of N-cadherin to the juxtaposed membranes between adjacent cells; the axon-guidance molecule Robo-1 mediated by ZEB-1 can reverse this process by severing the anchorage of N-cadherin to the cytoskeleton (181).…”

Impact of positive ZEB1 expression in patients with epithelial ovarian carcinoma as an oncologic outcome-predicting indicator

“…In fact, earlier studies reported that ZEB1 promotes tumor invasiveness and metastasis and is correlated with a poorer clinical prognosis in patients with several solid cancers (6)(7)(8). According to the prior report from Siebzehnrubl et al (9), ZEB1 is an important marker of glioblastoma recurrence, including the capability of evading chemotherapy, suggesting that this molecule acts in both glioblastoma invasion and chemoresistance. In addition, silencing ZEB1 expression could significantly restore the chemosensitivity of docetaxel-resistant human lung adenocarcinoma cells as well as inhibit their migratory ability through reversing the mesenchymal phenotype (10).…”