TMOD-03. CELL-OF-ORIGIN FOR GBM AND ITS APPLICATION FOR TRANSLATIONAL RESEARCH

Abstract

Glioma is a devastating disease because low-grade tumors inevitably progress into incurable high-grade GBMs. Among all probable explanations, such progressive nature could be attributed to the innate properties of its cell-of-origin. An ideal approach to identify the cell-of-origin for glioma is to analyze growth advantages of mutant cells in each brain cell types prior to malignancy. Our lab models glioma using a mouse genetic system called Mosaic Analysis with Double Markers (MADM), which generates GFPlabeled TSG-null cells and RFP-labeled sibling wildtype cells. By design, increased ratio of green-to-red cell numbers (G/R ratio) serves as the indication of tumor initiation long before malignancy. Using MADM, we found that after introducing p53/Nf1 mutations into neural stem cells (NSCs), significant aberrant expansion only occurred in oligodendrocyte precursor cells (OPCs, G/R ratio > 100), but not in any other NSC-derived lineages or NSCs themselves. Furthermore, introducing p53/Nf1 mutations directly into OPCs consistently led to gliomagenesis, further suggesting OPCs as the cell-of-origin in this model [Liu 2011 Cell]. Surprisingly, a close examination revealed a lack of overall OPC density increase in mutant brains in comparison to WT brains despite of the large G/R ratio, suggesting that green mutant OPCs actively out-compete WT OPCs to overtake the brain. Intrinsic competitive nature of OPCs could explain the inevitable progression of low-grade glioma since cells with “advantageous” mutations would kill other OPCs to make space for their own expansion. Under the same notion, traditional cytotoxic treatment could backfire by providing selective pressure that enriches resistant tumor cells. To look for alternative methods, we demonstrated that blocking the competitiveness of mutant OPCs with genetic methods completely prevented gliomagenesis in the mouse model. Currently, we are using cell culture-based assays and in vivo drug testing to identify potential anti-competition drugs that could be translated into clinical settings.