Transformation of quiescent adult oligodendrocyte precursor cells into malignant glioma through a multistep reactivation process

Abstract

How malignant gliomas arise in a mature brain remains a mystery, hindering the development of preventive and therapeutic interventions. We previously showed that oligodendrocyte precursor cells (OPCs) can be transformed into glioma when mutations are introduced perinatally. However, adult OPCs rarely proliferate compared with their perinatal counterparts. Whether these relatively quiescent cells have the potential to transform is unknown, which is a critical question considering the late onset of human glioma. Additionally, the premalignant events taking place between initial mutation and a fully developed tumor mass are particularly poorly understood in glioma. Here we used a temporally controllable Cre transgene to delete p53 and NF1 specifically in adult OPCs and demonstrated that these cells consistently give rise to malignant gliomas. To investigate the transforming process of quiescent adult OPCs, we then tracked these cells throughout the premalignant phase, which revealed a dynamic multistep transformation, starting with rapid but transient hyperproliferative reactivation, followed by a long period of dormancy, and then final malignant transformation. Using pharmacological approaches, we discovered that mammalian target of rapamycin signaling is critical for both the initial OPC reactivation step and late-stage tumor cell proliferation and thus might be a potential target for both glioma prevention and treatment. In summary, our results firmly establish the transforming potential of adult OPCs and reveal an actionable multiphasic reactivation process that turns slowly dividing OPCs into malignant gliomas.cancer | cellular quiescence | cellular reactivation | mTOR signaling

Individual roles of p53 and NF1 in OPC Competition and Gliomagenesis

“…In our previous studies, we found that, upon the introduction of p53/NF1 mutations into neural stem cells, cell lineage-specific analysis revealed a dramatic increase of G/R ratio at pre-malignant stage only in oligodendrocyte precursor cells (OPCs) but not in any other brain cell types (Liu et al, 2011b). Along with other evidences, we pinpointed OPC as the cell-of-origin in this model, a finding supported by other studies (Assanah et al, 2006;Galvao et al, 2014;Lindberg et al, 2009Lindberg et al, , 2014Persson et al, 2010). …”

“…Our early studies demonstrated that OPCs re-enter cell cycle (reactivation) at 12-day post injection (12 dpi) and subsequently transform into glioma at 180 dpi (Galvao et al, 2014). In this study, we further introduced floxed alleles of mTOR into the tumor model, which harbors p53 and NF1 deletions, to determine the necessity of mTOR in OPC transformation.…”

“…Thus, whether or not this system recapitulated the human disease was left unanswered. To resolve this issue, our lab then made use of a traditional condition knockout system (CKO) that allowed for p53 and NF1 deletion in OPCs using an NG2-CreER that is inducible upon tamoxifen administration (Galvao et al, 2014 (Chow et al, 2011;Friedmann-Morvinski et al, 2012;Uhrbom et al, 2002). While our findings were not the first to put forth the idea that OPCs are the cell of origin, our unique ability to label all neural cells and track the effects on all the cells gave us an unprecedented ability to analyze pre-malignant stages in addition to malignant stages.…”

“…Our previous data has shown that not only can OPCs serve as the cell origin and also that mutant cells have a limited capacity to differentiate and continually proliferate (Galvao et al, 2014;Liu et al, 2011a).…”

“…Additionally, the recovery of OPCs at 2 weeks could be from either surviving OPCs in the cortex or from neural stem cells (NSCs) residing in the SVZ. To address these issues we then used a tdTomato reporter under the control of NG2-CreER, an OPC-specific Cre that we have previously shown labels only OPCs but never NSCs (Galvao et al, 2014). At P10, mice were injected with Tamoxifen every other day for 8 days, followed by IR at P20, and then analysis at 1 week and 2 weeks to determine if these cells are truly ablated and if they come from tdTomato+ OPCs (Figure 3.16a).…”