Transposon mutagenesis identifies genes that transform neural stem cells into glioma-initiating cells

摘要: Neural stem cells (NSCs) are considered to be the cell of origin glioblastoma multiforme (GBM). However, genetic alterations that transform NSCs into glioma-initiating remain elusive. Using a unique transposon mutagenesis strategy mutagenizes in culture, followed by additional rounds generate tumors vivo, we have identified genes and signaling pathways can cells. Mobilization Sleeping Beauty transposons induced immortalization astroglial-like cells, which were then able with characteristics mesenchymal subtype GBM on transplantation, consistent potential astroglial for GBM. Sequence analysis insertion sites from immortalized more than 200 frequently mutated genes, including human GBM-associated such as Met Nf1, made it possible discriminate between function during vs. later stages tumor development. We also functionally validated five candidate using previously undescribed high-throughput method. Finally, show even clonally related derived same line acquired distinct combinations development, suggesting formation this model system involves competition among genetically variant is similar Darwinian evolutionary processes now thought many cancers. This faster simpler conventional screens potentially applied any tissue stem/progenitor grown differentiated vitro.