Abstract 4906: ZEB1 maintains self-renewal, invasion and chemoresistance of glioblastoma stem cells.

Abstract

Abstract Despite intense efforts in basic research and clinical medicine, glioblastoma remains one of the most lethal types of cancer. In particular, tumor recurrence after surgical resection, targeted radiation, and aggressive chemotherapy remains an insurmountable obstacle. Recurrence has been attributed to residual cancer cells that re-initiate tumor growth after primary clinical intervention. Hierarchical attribution of this capacity for tumor (re-)initiation to a specific cellular subpopulation is one of the hallmarks of the cancer stem cell hypothesis. In cancers outside the CNS, a considerable overlap between cancer stem cell phenotypes and Epithelial-Mesenchymal-Transition (EMT) has been found. EMT is frequently associated with distant spreading and the generation of secondary tumors. Tumor cells undergoing EMT have a higher propensity for invasion and therapy resistance, as well as greater stemness potential. Transcription factors regulating EMT, including ZEB1 (zinc finger E-box binding homeobox 1), have been found to regulate typical stem cell-associated genes. We therefore tested whether the EMT-associated transcription factor ZEB1 may coordinate mechanisms of invasion, therapy resistance and recurrence in glioblastoma. ZEB1 is preferentially expressed at the tumor invasion front, and its knockdown results in a dramatic reduction of tumorigenicity, invasion and increased sensitivity to the chemotherapeutic agent Temozolomide (Temodar®, TMZ). We found that ZEB1 indirectly controls expression of the chemoresistance-mediating enzyme MGMT (O-6-Methylguanine DNA Methyltransferase), as well as cell-cell adhesion and stemness pathways, thus linking chemoresistance and invasion in brain cancer stem cells. Moreover, ZEB1 expression in glioblastoma patients is predictive of shorter survival and poor TMZ response. These results indicate that invasive glioblastoma cells are particularly sheltered from current therapeutic approaches, rendering them likely candidates for tumor recurrence. This offers a potential novel model for GBM recurrence, and a potential therapeutic target. Citation Format: Florian A. Siebzehnrubl, Daniel J. Silver, Bugra Tugertimur, Loic P. Deleyrolle, Dorit Siebzehnrubl, Matthew R. Sarkisian, Kelly G. Devers, Antony T. Yachnis, Marius D. Kupper, Daniel Neal, Nancy H. Nabilsi, Michael P. Kladde, Oleg Suslov, Simone Brabletz, Thomas Brabletz, Brent A. Reynolds, Dennis A. Steindler. ZEB1 maintains self-renewal, invasion and chemoresistance of glioblastoma stem cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4906. doi:10.1158/1538-7445.AM2013-4906