title: 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.
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403;
authors.forename: Rui Pedro
authors.initials: RP
authors.lastname: Galvao
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403;
authors.forename: Anita
authors.initials: A
authors.lastname: Kasina
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599;
authors.forename: Robert S
authors.initials: RS
authors.lastname: McNeill
authors.affiliation: Department of Biological Sciences, California Polytechnic State University, San Luis Obispo, CA 93401;
authors.forename: Jordan E
authors.initials: JE
authors.lastname: Harbin
authors.affiliation: Department of Pathology, Genentech, South San Francisco, CA 94080;
authors.forename: Oded
authors.initials: O
authors.lastname: Foreman
authors.affiliation: Department of Genomic Medicine, Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030;
authors.forename: Roel G W
authors.initials: RG
authors.lastname: Verhaak
authors.affiliation: Department of Physiology and Neurobiology, University of Connecticut, Storrs, CT 06269;
authors.forename: Akiko
authors.initials: A
authors.lastname: Nishiyama
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, NC 27599; Lineberger Comprehensive Cancer Center, Neurosciences Center, and Department of Neurology, University of North Carolina School of Medicine, Chapel Hill, NC 27599; and.
authors.forename: C Ryan
authors.initials: CR
authors.lastname: Miller
authors.affiliation: Institute of Molecular Biology, University of Oregon, Eugene, OR 97403; Department of Microbiology, Immunology, and Cancer Biology, University of Virginia, Charlottesville, VA 22908 hz9s@virginia.edu.
authors.forename: Hui
authors.initials: H
authors.lastname: Zong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D020869:Gene Expression Profiling; D005910:Glioma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D025542:Neurofibromin 1 / Q000235:genetics / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013629:Tamoxifen / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D025542:Neurofibromin 1; D016159:Tumor Suppressor Protein p53; D013629:Tamoxifen; C401859:temsirolimus; D020123:Sirolimus
keywords: cancer; cellular quiescence; cellular reactivation; mTOR signaling