title: Olig2-Dependent Reciprocal Shift in PDGF and EGF Receptor Signaling Regulates Tumor Phenotype and Mitotic Growth in Malignant Glioma.
abstract: 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 an astroglia-associated gene expression pattern, manifest in downregulation of platelet-derived growth factor receptor-α and reciprocal upregulation of epidermal growth factor receptor (EGFR). Olig2 deletion further sensitizes glioma cells to EGFR inhibitors and extends the lifespan of animals. Thus, Olig2-orchestrated receptor signaling drives mitotic growth and regulates glioma phenotypic plasticity. Targeting Olig2 may circumvent resistance to EGFR-targeted drugs.
authors.affiliation: Laboratory of Pathology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu 610041, China; Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA.
authors.forename: Fanghui
authors.initials: F
authors.lastname: Lu
authors.affiliation: School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA.
authors.forename: Chuntao
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA.
authors.forename: Haibo
authors.initials: H
authors.lastname: Wang
authors.affiliation: Department of Pathology & Integrative Biology Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Danyang
authors.initials: D
authors.lastname: He
authors.affiliation: Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA.
authors.forename: Lingli
authors.initials: L
authors.lastname: Xu
authors.affiliation: Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA.
authors.forename: Jincheng
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA.
authors.forename: Xuelian
authors.initials: X
authors.lastname: He
authors.affiliation: Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA.
authors.forename: Yaqi
authors.initials: Y
authors.lastname: Deng
authors.affiliation: Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA.
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Lu
authors.affiliation: School of Life Sciences, Xiamen University, Fujian 361102, China.
authors.forename: Xue
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA.
authors.forename: Ravinder
authors.initials: R
authors.lastname: Verma
authors.affiliation: Laboratory of Pathology, State Key Laboratory of Biotherapy, West China Hospital, Sichuan University and National Collaborative Innovation Center, Chengdu 610041, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Bu
authors.affiliation: Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA.
authors.forename: Rachid
authors.initials: R
authors.lastname: Drissi
authors.affiliation: Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA.
authors.forename: Maryam
authors.initials: M
authors.lastname: Fouladi
authors.affiliation: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Anat O
authors.initials: AO
authors.lastname: Stemmer-Rachamimov
authors.affiliation: Department of Pathology & Integrative Biology Program, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Dennis
authors.initials: D
authors.lastname: Burns
authors.affiliation: Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA.
authors.forename: Mei
authors.initials: M
authors.lastname: Xin
authors.affiliation: Departments of Pediatrics and Anatomy and Neurobiology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Rubin
authors.affiliation: Department of Internal Medicine, UC Brain Tumor Center, University of Cincinnati, Cincinnati, OH 45267, USA.
authors.forename: El Mustapha
authors.initials: EM
authors.lastname: Bahassi
authors.affiliation: Department of Pathology & Cellular Biology, Columbia University Medical Center, New York, NY 10032, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Canoll
authors.affiliation: 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.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
authors.affiliation: Department of Pediatrics, Division of Experimental Hematology and Cancer Biology, Brain Tumor Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 25229, USA; Key Laboratory of Birth Defects, Children's Hospital of Fudan University, Shanghai 201102, China. Electronic address: richard.lu@cchmc.org.
authors.forename: Q Richard
authors.initials: QR
authors.lastname: Lu
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000378:metabolism; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics*; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism; D009836:Oligodendroglia / Q000378:metabolism; D010641:Phenotype; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics; D018874:Spheroids, Cellular / Q000378:metabolism; D016019:Survival Analysis
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D066246:ErbB Receptors; D009419:Nerve Tissue Proteins; D017479:Receptors, Platelet-Derived Growth Factor