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Opposing Tumor-Promoting and -Suppressive Functions of Rictor/mTORC2 Signaling in Adult Glioma and Pediatric SHH Medulloblastoma.
Akgül, Seçkin; Li, Yinghua; Zheng, Siyuan; Kool, Marcel; Treisman, Daniel M; Li, Chaoyang; Wang, Yuan; Gröbner, Susanne; Ikenoue, Tsuneo; Shen, Yiping; Camelo-Piragua, Sandra; Tomasek, Gerald; Stark, Sebastian; Guduguntla, Vinay; Gusella, James F; Guan, Kun-Liang; Pfister, Stefan M; Verhaak, Roel G W; Zhu, Yuan.
Afiliação
  • Akgül S; Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Gilbert Family Neurofibromatosis Institute, Children's National Medical Center, Washingt
  • Li Y; Gilbert Family Neurofibromatosis Institute, Children's National Medical Center, Washington, DC 20010, USA; Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA; Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20
  • Zheng S; Greehey Children's Cancer Research Institute, The University of Texas Health Science Center at San Antonio, San Antonio, TX 78229, USA.
  • Kool M; Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
  • Treisman DM; Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Gilbert Family Neurofibromatosis Institute, Children's National Medical Center, Washingt
  • Li C; Gilbert Family Neurofibromatosis Institute, Children's National Medical Center, Washington, DC 20010, USA; Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA; Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20
  • Wang Y; Gilbert Family Neurofibromatosis Institute, Children's National Medical Center, Washington, DC 20010, USA; Center for Cancer and Immunology Research, Children's National Medical Center, Washington, DC 20010, USA; Center for Neuroscience Research, Children's National Medical Center, Washington, DC 20
  • Gröbner S; Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
  • Ikenoue T; Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Shen Y; Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • Camelo-Piragua S; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Tomasek G; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Stark S; Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany.
  • Guduguntla V; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA.
  • Gusella JF; Center for Genomic Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
  • Guan KL; Department of Pharmacology and Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA.
  • Pfister SM; Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), 69120 Heidelberg, Germany; Department of Hematology and Oncology, Heidelberg University Hospital, 6912
  • Verhaak RGW; Jackson Laboratory for Genomic Medicine, Farmington, CT 06032, USA.
  • Zhu Y; Cellular and Molecular Biology Graduate Program, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA; Gilbert Family Neurofibromatosis Institute, Children's National Medical Center, Washingt
Cell Rep ; 24(2): 463-478.e5, 2018 07 10.
Article em En | MEDLINE | ID: mdl-29996106
ABSTRACT
Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem cell niche. Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53 mutant sonic hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Proteínas Hedgehog / Alvo Mecanístico do Complexo 2 de Rapamicina / Proteína Companheira de mTOR Insensível à Rapamicina / Glioma / Meduloblastoma Tipo de estudo: Prognostic_studies Limite: Adult / Animals / Child / Humans Idioma: En Revista: Cell Rep Ano de publicação: 2018 Tipo de documento: Article
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Transdução de Sinais / Proteínas Hedgehog / Alvo Mecanístico do Complexo 2 de Rapamicina / Proteína Companheira de mTOR Insensível à Rapamicina / Glioma / Meduloblastoma Tipo de estudo: Prognostic_studies Limite: Adult / Animals / Child / Humans Idioma: En Revista: Cell Rep Ano de publicação: 2018 Tipo de documento: Article