Tmod-03. cell-of-origin for gbm and its application for translational research

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 GFP-labeled 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...
Source: Neuro-Oncology - Category: Cancer & Oncology Authors: Tags: TUMOR MODELS Source Type: research