Exploring the Therapeutic Potential of Stem Cell Biology in Gliomas

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

We have performed experiments to improve our understanding of the molecular mechanisms of deregulated differentiation pathways in TSCs: The delicate balance between stem cell self-renewal and differentiation is controlled by various cell intrinsic and extrinsic factors that are critical for normal tissue homeostasis. Despite extensive phenotypic and functional similarities between GSCs and normal stem cells, the differentiation potentials of GSCs are not entirely normal. Elucidation of the differentiation pathways that are operative in both normal stem cells and GSCs will be critical for fully understanding tumorigenesis and will likely lead to novel therapeutic targets. We have also identified a set of deregulated differentiation pathways in GSCs derived from human primary GBM. Elucidation of underlying molecular mechanism will provide important clues for predicting sensitivity of differentiation therapeutic approach. Characterization of TSCs in aspect of differentiation-inducing agents further revealed the limitations of traditional glioma cell lines grown in serum. For example, retinoic acid treatment and CNTF exposure potently induce differentiation in most GBM tumor initiate cells (TICs) but not of traditional cell lines. This prompted us to question whether many of potential tumor suppressors and/or cytostatic genes previously studied in cell lines, were not recognized. Given the ever-increasing number of potential GSGs and oncogenes in glioblastoma TSCs identified from bioinformatics approaches and technical expertise of stem cell culture accumulated in the laboratories, we have set up screening systems to study the function of these genes in stem cell cultures. In addition, we have made significant progress on one of keystone projects that is to understand the genomic and molecular signaling similarities and differences between our glioma TSCs and normal neural stem cells (NSC). We have performed a very large scale study of 7 different GBM-derived TSCs and normal embryonic NSC lines under both proliferative and differentiating conditions and derived high-throughput mRNA and microRNAs profiling. Since November of 2014, when Dr Gilbert initiated the new glioma stem cell translational study project, we have created 6 more glioma-derived TSCs, introduced 3 IDH- mutated TSCs, and subsequently performed the computational analyses for characterization of the genetics and signaling pathways in these GSCs, enabling these cell lines to be used to explore the therapeutic potential of glioma stem cell biology, such as metabolic changes and immunological reactions. Additionally, we have through collaborations and Material Transfer Agreements obtained important cell lines that provide an outstanding resource for the laboratory. In total, there are now 62 human tumor lines in the NOB Laboratory. As part of this project, each of these cell lines has been extensively molecularly characterized including whole exome sequencing, analysis of the methylome and RNA sequencing. These data are being uploaded into a database system to enable analysis and selection of optimal model systems for preclinical studies for all of the research groups in the NOB.