An RNAi Screen Identifies TRRAP as a Regulator of Brain Tumor-Initiating Cell Differentiation

Heiko Wurdak, Shoutian Zhu, Angelica Romero, Mihaela Lorger, James Watson, Chih yuan Chiang, Jay Zhang, Vanita S. Natu, Luke L. Lairson, John R. Walker, Christopher M. Trussell, Griffith R. Harsh, Hannes Vogel, Brunhilde Felding-Habermann, Anthony P. Orth, Loren J. Miraglia, Daniel R. Rines, Stephen L. Skirboll, Peter G. Schultz

Research output: Contribution to journalArticlepeer-review

85 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)37-47
Number of pages11
JournalCell Stem Cell
Volume6
Issue number1
DOIs
StatePublished - Jan 8 2010
Externally publishedYes

Keywords

  • CELLCYCLE
  • STEMCELL

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Cell Biology

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