Stem-31. Targeting Glioblastoma Stem Cells by Perturbing a Novel Gene Regulatory Cluster to Reduce Tumor Recurrence
Year: 2017
Type: conference-abstract
Abstract: Glioblastoma (GBM) is the most prevalent and aggressive brain cancer in adults. GBM is enriched with 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 the dearth of knowledge of master regulators specific to GSCs and not to normal brain cells. Therefore systematic elucidation of the GSC-specific core regulatory program will improve our understanding of GSC biology and provide an opportunity to develop novel GSC-specific therapy with maximal efficacy and minimal toxicity. To accomplish these objectives, we have recently developed two innovative computational platforms, GeneRep and nSCORE and experimentally validated them in several published datasets. 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 belonging 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 knock down by siRNA compared to depletion of 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.
Source: Neuro-Oncology
Institution: University of Florida
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2767581356