Model development Since the initiation of this project last year, we have successfully established in vitro models for IDH1-mutated glioma based on lentivirus-based knock-in system. These includes constitutive expression, bi-cistronic and inducible IDH1 mutant expression cell lines. Our group also adopted patient derived IDH1-mutated cell lines for molecular study and xenograft generation. Discover molecular signature in IDH1-mutated glioma By working with bioinformatics teams in NOB and CCR, we investigated the transcriptomic profile in IDH1-mutated glioma cells by RNA sequencing. Molecular pathways that govern cellular motility, migration and invasion were found substantially up-regulated in IDH1-mutated cells. We followed this finding by a series of molecular and cellular assays, and confirmed that acquisition of IDH1 mutation enhances cytoskeleton polymerization, small GTPase and plasma membrane motility. Mechanistically, the depletion of TCA cycle in IDH1-mutated cells activate mTORC2 complex by up-regulating a key regulatory unit Rictor. The mTORC2/Rictor complex enhances the cell locomotion and mobility via its concomitant downstream small GTPase rac1. Pharmacologic inhibition of mTORC2 or rac1 activation suppress cellular motility and metabolite internalization. This novel mTORC2/Rictor/Rac1 pathway introduces a novel mechanism for IDH1-mutated cells for cell motility and metabolite internalization, so that damaged metabolic pathways could be compensated by enhanced food-seeking pattern. Develop novel therapeutic strategy to IDH1-mutated glioma Considering their essential roles in metabolic compensation for IDH1-mutated cells, targeting mTORC2/Rac1 pathway could be helpful to suppress cancers with IDH1 mutation. To investigate this, we established Rac1 knockdown cells in patient derived IDH1-mutated cells. Currently we are testing this model for intracranial xenograft model. Tumor progression and disease outcome will be followed upon the availability of xenograft model. Our team is also trying targeting mTORC2/Rac1 pathway by small molecular compounds, seeking for more therapeutic options available.
|Pang, Ying; Lu, Yanxin; Caisova, Veronika et al. (2018) Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma. Clin Cancer Res 24:3423-3432|