Glioblastoma (GBM) is the most common and deadliest malignant brain tumor in adults. GBM is enriched in glioma stem-like cells (GSCs) that contribute to tumor initiation and treatment resistance and thus a natural focus for therapeutic development. However, targeting GSCs has been a challenge because of a lack of master regulators specific to GSCs and not to normal brain cells. Therefore, systematic identification of the GSC-specific common regulatory program will improve our understanding of GSCs and provide an opportunity to develop GSC-specific therapeutics that are efficacious and safe. To accomplish these objectives, we have recently developed two innovative tandem computational platforms, GeneRep and nSCORE, which were subsequently experimentally validated. The tandem platforms complement each other and allow us to 1) interrogate large-scale gene expression profiles of GSCs, GBM-differentiated cells, normal neuronal precursor cells (NPCs) and astrocytes (NAs) to extract candidate GSC-specific gene regulatory networks; and 2) functionally rank GSC-specific core master regulators, respectively. A cluster of 8 interrelated master subnetworks emerged, which were functionally grouped into the stemness and cancer pathways, some of which belonged to the Sox, Olig and Myc families. By enforcing the expression of this cluster in NAs, we were able to reprogram these normal cells into GSCs as measured by the neurosphere formation and in vivo tumorigenesis assays, confirming the critical requirement of this cluster for the GSC identity. Furthermore, this network cluster was present and functioned cooperatively to maintain GSCs in several patient-derived GSC lines examined to date. Survival and neurosphere formation rates of GSCs were profoundly suppressed when at least two nodes in this cluster were depleted by siRNA compared to depletion of the individual nodes. Our data establish a novel gene regulatory cluster controlling GSCs and provide a compelling rationale for its therapeutic targeting to reduce tumor recurrence.

Citation Format: Changwang Deng, Son B. Le, David D. Tran. A novel regulatory gene subnetwork of glioma stem-like cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1141.