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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 40; pp. E4214 - E4223
• Main Authors: Galvao, Rui Pedro, Kasina, Anita, McNeill, Robert S, Harbin, Jordan E, Foreman, Oded, Verhaak, Roel G W, Nishiyama, Akiko, Miller, C Ryan, Zong, Hui
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 07.10.2014; National Acad Sciences
• Series: PNAS Plus
• Subjects: Animals; Antineoplastic Agents - pharmacology; Biological Sciences; Blotting, Western; Brain; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Differentiation - drug effects; Cell Differentiation - genetics; Cell Proliferation - drug effects; Cell Proliferation - genetics; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Cells; Gene Expression Profiling; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Immunohistochemistry; Intervention; Mice, Inbred NOD; Mice, Knockout; Mice, SCID; Mice, Transgenic; Mutation; Neural Stem Cells - cytology; Neural Stem Cells - metabolism; Neurofibromin 1 - genetics; Neurofibromin 1 - metabolism; Oligodendroglia - cytology; Oligodendroglia - metabolism; Oligonucleotide Array Sequence Analysis; PNAS Plus; Sirolimus - analogs & derivatives; Sirolimus - pharmacology; Tamoxifen - pharmacology; Tumor Cells, Cultured; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Protein p53 - metabolism; Tumors; cancer; mTOR signaling; cellular quiescence; cellular reactivation
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1414389111

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. Significance How malignant gliomas arise in a mature brain remains a mystery, which hinders the development of effective treatments. Which cell types can escape their quiescent, adult state and how they do so is unknown. Additionally, because gliomas are only detected at advanced stages, the full course of transformation remains uncharacterized. Here we report that adult oligodendrocyte precursor cells, despite their relatively quiescent properties, can be reactivated to a highly proliferative state by p53 and NF1 mutations and give rise to malignant gliomas. Furthermore, we describe the early phase of gliomagenesis for the first time, revealing a multistep process of reactivation, dormancy, and final transformation in which mammalian target of rapamycin signaling plays a critical role at both early and late steps.