Abstract 351: Gliomagenesis via the reactivation of quiescent adult oligodendrocyte precursor cells.

Abstract

Abstract Malignant gliomas are devastating, incurable brain tumors. Surprisingly, though the proliferative activity of brain cells decreases precipitously with age, glioma occurs most frequently in the elderly. Our lab recently showed that introducing p53 and NF1 mutations into perinatal oligodendrocyte precursor cells (OPCs) can lead to gliomagenesis. However, perinatal OPCs are highly migratory and proliferative, whereas adult OPCs are much more quiescent. Therefore, to better understand the impact of age on gliomagenesis, we asked if adult OPCs can be transformed into gliomas, and if so, what would be the reactivating mechanisms. Using NG2-CreER, a temporally controllable Cre, we introduced p53/NF1 mutations specifically into adult OPCs by giving Tamoxifen (Tmx) to young adult (P45) and aging mice (P180). We found that gliomas formed with high penetrance in both groups. Notably, tumor latency of both groups was very similar (120-180 days post-Tmx), suggesting that OPC transforming potential does not decrease as the brain ages. Adult OPC-derived tumors have pathological features of malignant anaplastic (grade III) glioma and a transcriptional profile similar to human proneural glioma. Interestingly, these features are comparable to gliomas derived from embryonic neural stem cells and perinatal OPCs, indicating that the age at which mutations arise does not influence tumor type. The transcriptional profile of adult OPC-derived tumor cells closely matched that of wild type perinatal OPCs, suggesting that tumor OPCs have been rejuvenated. To identify when mutant OPCs first become reactivated, we analyzed brain regions where these tumors tend to occur (olfactory bulb, thalamus, pyriform cortex, amygdala) at various time points after mutation. At both 50 and 90 days post-Tmx, the number of mutant OPCs was 6-fold higher than that of WT OPCs, indicating pre-malignant over-expansion of these cells. Surprisingly, mutant OPC proliferation was not increased at either time point. Further analysis showed that mutant OPCs have defects in differentiation into mature oligodendrocytes. These results suggest that mutant OPCs become reactivated soon after mutagenesis, and that their inability to differentiate might play a role in malignant transformation. To understand the molecular mechanisms of adult OPC reactivation, we are currently investigating the involvement of signal transduction pathways known to play important roles in early OPC development. In summary, our results show that, despite being mostly quiescent, adult OPCs have the potential to become reactivated by the loss of tumor suppressor genes and can give rise to malignant gliomas. Signaling pathways with known roles in early OPC development might once again play a role in malignant transformation of these cells in the adult brain. Therefore, studying gliomagenesis and OPC development in parallel could lead to novel strategies for treating these deadly tumors. Citation Format: Rui P. Galvao, Roeland G. W. Verhaak, Oded Foreman, Hui Zong. Gliomagenesis via the reactivation of quiescent adult oligodendrocyte precursor cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 351. doi:10.1158/1538-7445.AM2013-351