Year: 2017
Type: conference-abstract
Abstract: IDH-mutant (IDH-MUT) glioma patients show highly improved prognosis compared to those with wild-type IDH. However, IDH mutations are rare in the more aggressive grade IV glioblastomas and introducing IDH mutations in mouse neural cells does not induce gliomagenesis. This is a paradox, given that IDH mutation is considered an early oncogenic event and the mutated IDH produces the oncometabolite 2-hydroxyglutarate. Here we identify a previously unknown mechanism that explains this paradox. We found that IDH-MUT patient tumors expressing a molecular signature enriched in genes associated with neuronal differentiation survive the longest (~11 years) and these same tumors have significantly lower expression of the Mesenchymal master regulator TAZ, which is epigenetically silenced. Concordantly, IDH-MUT/TAZ-low glioma stem-like cells (GSCs) show remarkable neuronal differentiation induced by retinoic acid, whereas IDH-WT/TAZ-high GSCs are resistant to this process implying that IDH status and TAZ levels dictate propensity to neurogenesis. TAZ overexpression in IDH-MUT GSCs caused inhibition of retinoic acid neuronal differentiation and conversely CRISPR/Cas9-mediated knockout of TAZ in IDH-WT GSCs promotes this process as judged by alteration in genes regulating neurogenesis as well as cellular morphology resembling neurons (dendritic branching etc.). Furthermore, injection of TAZ in the dorsal ectoderm of Xenopus embryos caused a defect in neural development affirming the role of TAZ as a negative regulator of neurogenesis. We are currently examining the mechanisms by which TAZ blocks neurogenesis and the in vivo consequences of concomitant TAZ knockout with retinoic acid treatment in intracranial models. Taken together, our studies uncover a role for TAZ as a barrier for terminal neuronal differentiation and that differentiation therapy with retinoic acid is possible for IDH-WT gliomas if combined with a TAZ inhibitor.
Source: Neuro-Oncology
Institution: The University of Texas MD Anderson Cancer Center
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: bronze
OpenAlex ID: W2768035720