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      Olig2-Dependent Reciprocal Shift in PDGF and EGF Receptor Signaling Regulates Tumor Phenotype and Mitotic Growth in Malignant Glioma

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          Summary

          Malignant gliomas exhibit extensive heterogeneity and poor prognosis. Here we identify mitotic Olig2-expressing cells as tumor-propagating cells in proneural gliomas, elimination of which blocks tumor initiation and progression. Intriguingly, deletion of Olig2 resulted in tumors that grow, albeit at a decelerated rate. Genome occupancy and expression profiling analyses reveal that Olig2 directly activates cell proliferation machinery to promote tumorigenesis. Olig2 deletion causes a tumor phenotypic shift from an oligodendrocyte precursor-correlated proneural toward astroglia-associated gene expression pattern, manifest in down-regulation of PDGF receptor-alpha and reciprocal up-regulation of EGFR. Olig2 deletion further sensitizes glioma cells to EGFR inhibitors and extends animal lifespans. Thus, Olig2-orchestrated receptor signaling drives mitotic growth and regulates glioma phenotypic plasticity. Targeting Olig2 may circumvent resistance to EGFR-targeted drugs.

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          Lu et al. show that ablation of dividing Olig2-expressing cells in a glioma model reduces tumor initiation and growth. Olig2 deletion in glioma also delays growth, changes the gene expression profile from proneural to classical subtype, and leads to increased EGFR expression and sensitivity to EGFR inhibitors.

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          Author and article information

          Journal
          101130617
          29778
          Cancer Cell
          Cancer Cell
          Cancer cell
          1535-6108
          1878-3686
          12 July 2016
          9 May 2016
          09 May 2017
          : 29
          : 5
          : 669-683
          Affiliations
          [1 ]Laboratory of Pathology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu, 610041, China
          [2 ]Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 25229, USA
          [3 ]School of Life Sciences, Xiamen University, Fujian, 361102, China
          [4 ]Department of Pathology & Integrative Biology Program, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
          [5 ]Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
          [6 ]Departments of Pediatrics and Anatomy and Neurobiology, Washington University School of Medicine, St Louis, Missouri, USA
          [7 ]Department of Internal Medicine, UC Brain Tumor Center, University of Cincinnati, Cincinnati OH, USA
          [8 ]Department of Pathology & Cellular Biology, Columbia University Medical Center, New York, NY 10032, USA
          [9 ]Division of Human Biology and Solid Tumor Translational Research, Fred Hutchinson Cancer Research Center, Alvord Brain Tumor Center, University of Washington, Seattle, WA 98109, USA
          [10 ]Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai, China, 201102
          Author notes
          Correspondence: Q. Richard Lu, Department of Pediatrics, Brain Tumor Center, Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, OH 25229, USA; Tel: 513-636-7684; Fax: 513-803-0783; richard.Lu@ 123456cchmc.org
          Article
          PMC4946168 PMC4946168 4946168 nihpa774896
          10.1016/j.ccell.2016.03.027
          4946168
          27165742
          04846978-687c-490a-a095-3f0838d2b02c
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