title: An RNAi screen identifies TRRAP as a regulator of brain tumor-initiating cell differentiation.
abstract: Glioblastoma multiforme (GBM) is a highly aggressive form of brain cancer associated with a very poor prognosis. Recently, the initiation and growth of GBM has been linked to brain tumor-initiating cells (BTICs), which are poorly differentiated and share features with neural stem cells (NSCs). Here we describe a kinome-wide RNA interference screen to identify factors that control the tumorigenicity of BTICs. We identified several genes whose silencing induces differentiation of BTICs derived from multiple GBM patients. In particular, knockdown of the adaptor protein TRRAP significantly increased differentiation of cultured BTICs, sensitized the cells to apoptotic stimuli, and negatively affected cell cycle progression. TRRAP knockdown also significantly suppressed tumor formation upon intracranial BTIC implantation into mice. Together, these findings support a critical role for TRRAP in maintaining a tumorigenic, stem cell-like state.
authors.affiliation: The Skaggs Institute of Chemical Biology and Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Heiko
authors.initials: H
authors.lastname: Wurdak
authors.forename: Shoutian
authors.initials: S
authors.lastname: Zhu
authors.forename: Angelica
authors.initials: A
authors.lastname: Romero
authors.forename: Mihaela
authors.initials: M
authors.lastname: Lorger
authors.forename: James
authors.initials: J
authors.lastname: Watson
authors.forename: Chih-Yuan
authors.initials: CY
authors.lastname: Chiang
authors.forename: Jay
authors.initials: J
authors.lastname: Zhang
authors.forename: Vanita S
authors.initials: VS
authors.lastname: Natu
authors.forename: Luke L
authors.initials: LL
authors.lastname: Lairson
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Trussell
authors.forename: Griffith R
authors.initials: GR
authors.lastname: Harsh
authors.forename: Hannes
authors.initials: H
authors.lastname: Vogel
authors.forename: Brunhilde
authors.initials: B
authors.lastname: Felding-Habermann
authors.forename: Anthony P
authors.initials: AP
authors.lastname: Orth
authors.forename: Loren J
authors.initials: LJ
authors.lastname: Miraglia
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Rines
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Skirboll
authors.forename: Peter G
authors.initials: PG
authors.lastname: Schultz
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis* / Q000235:genetics; D000818:Animals; D017209:Apoptosis; D001932:Brain Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D002454:Cell Differentiation; D002471:Cell Transformation, Neoplastic / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000737:chemistry* / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000737:chemistry* / Q000166:cytology; D009687:Nuclear Proteins / Q000032:analysis* / Q000235:genetics; D034622:RNA Interference; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D009687:Nuclear Proteins; C113829:transformation-transcription domain-associated protein