title: Oncogenes Activate an Autonomous Transcriptional Regulatory Circuit That Drives Glioblastoma.
abstract: Efforts to identify and target glioblastoma (GBM) drivers have primarily focused on receptor tyrosine kinases (RTKs). Clinical benefits, however, have been elusive. Here, we identify an SRY-related box 2 (SOX2) transcriptional regulatory network that is independent of upstream RTKs and capable of driving glioma-initiating cells. We identified oligodendrocyte lineage transcription factor 2 (OLIG2) and zinc-finger E-box binding homeobox 1 (ZEB1), which are frequently co-expressed irrespective of driver mutations, as potential SOX2 targets. In murine glioma models, we show that different combinations of tumor suppressor and oncogene mutations can activate Sox2, Olig2, and Zeb1 expression. We demonstrate that ectopic co-expression of the three transcription factors can transform tumor-suppressor-deficient astrocytes into glioma-initiating cells in the absence of an upstream RTK oncogene. Finally, we demonstrate that the transcriptional inhibitor mithramycin downregulates SOX2 and its target genes, resulting in markedly reduced proliferation of GBM cells in vivo.
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Dinesh K
authors.initials: DK
authors.lastname: Singh
authors.affiliation: Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Rahul K
authors.initials: RK
authors.lastname: Kollipara
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Vamsidara
authors.initials: V
authors.lastname: Vemireddy
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xiao-Li
authors.initials: XL
authors.lastname: Yang
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Yuxiao
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Nanda
authors.initials: N
authors.lastname: Regmi
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Stefan
authors.initials: S
authors.lastname: Klingler
authors.affiliation: Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Kimmo J
authors.initials: KJ
authors.lastname: Hatanpaa
authors.affiliation: Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jack
authors.initials: J
authors.lastname: Raisanen
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Steve K
authors.initials: SK
authors.lastname: Cho
authors.affiliation: Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shyam
authors.initials: S
authors.lastname: Sirasanagandla
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Suraj
authors.initials: S
authors.lastname: Nannepaga
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Sara
authors.initials: S
authors.lastname: Piccirillo
authors.affiliation: Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Mashimo
authors.affiliation: Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Shan
authors.initials: S
authors.lastname: Wang
authors.affiliation: Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Caroline G
authors.initials: CG
authors.lastname: Humphries
authors.affiliation: Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Neurological Surgery, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Bruce
authors.initials: B
authors.lastname: Mickey
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Maher
authors.affiliation: Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
authors.forename: Hongwu
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Albert Einstein Cancer Center, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Ryung S
authors.initials: RS
authors.lastname: Kim
authors.affiliation: Eugene McDermott Center for Human Growth and Development, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: ralf.kittler@utsouthwestern.edu.
authors.forename: Ralf
authors.initials: R
authors.lastname: Kittler
authors.affiliation: Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Annette G. Strauss Center for Neuro-Oncology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: robert.bachoo@utsouthwestern.edu.
authors.forename: Robert M
authors.initials: RM
authors.lastname: Bachoo
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004195:Disease Models, Animal; D015536:Down-Regulation / Q000187:drug effects; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D005909:Glioblastoma / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D060787:Neoplasm Grading; D000076104:Oligodendrocyte Transcription Factor 2 / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids / Q000235:genetics / Q000378:metabolism; D008926:Plicamycin / Q000494:pharmacology; D011799:Quinazolines / Q000627:therapeutic use; D034622:RNA Interference; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000071799:Zinc Finger E-box-Binding Homeobox 1 / Q000235:genetics* / Q000378:metabolism
chemical_list: D000076104:Oligodendrocyte Transcription Factor 2; D011799:Quinazolines; D055748:SOXB1 Transcription Factors; D000071799:Zinc Finger E-box-Binding Homeobox 1; D066246:ErbB Receptors; D020796:Receptor, Platelet-Derived Growth Factor alpha; D008926:Plicamycin; D000077156:Gefitinib
keywords: astrocyte; brain; cancer; glioblastoma; oncogene; stem cells; targeted therapy; transcription factor