Definition of genetic events directing the development of distinct types of brain tumors from postnatal neural stem/progenitor cells

Falk Hertwig, Katharina Meyer, Sebastian Braun, Sara Ek, Rainer Spang, Cosima V. Pfenninger, Isabella Artner, Gaëlle Prost, Xinbin Chen, Jaclyn A. Biegel, Alexander R. Judkins, Elisabet Englund, Ulrike A. Nuber

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Although brain tumors are classified and treated based upon their histology, the molecular factors involved in the development of various tumor types remain unknown. In this study, we show that the type and order of genetic events directs the development of gliomas, central nervous system primitive neuroectodermal tumors, and atypical teratoid/rhabdoid-like tumors from postnatal mouse neural stem/progenitor cells (NSC/NPC). We found that the overexpression of specific genes led to the development of these three different brain tumors from NSC/NPCs, and manipulation of the order of genetic events was able to convert one established tumor type into another. In addition, loss of the nuclear chromatin-remodeling factor SMARCB1 in rhabdoid tumors led to increased phosphorylation of eIF2α, a central cytoplasmic unfolded protein response (UPR) component, suggesting a role for the UPR in these tumors. Consistent with this, application of the proteasome inhibitor bortezomib led to an increase in apoptosis of human cells with reduced SMARCB1 levels. Taken together, our findings indicate that the order of genetic events determines the phenotypes of brain tumors derived from a common precursor cell pool, and suggest that the UPR may represent a therapeutic target in atypical teratoid/rhabdoid tumors.

Original languageEnglish (US)
Pages (from-to)3381-3392
Number of pages12
JournalCancer Research
Volume72
Issue number13
DOIs
StatePublished - Jul 1 2012

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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    Hertwig, F., Meyer, K., Braun, S., Ek, S., Spang, R., Pfenninger, C. V., Artner, I., Prost, G., Chen, X., Biegel, J. A., Judkins, A. R., Englund, E., & Nuber, U. A. (2012). Definition of genetic events directing the development of distinct types of brain tumors from postnatal neural stem/progenitor cells. Cancer Research, 72(13), 3381-3392. https://doi.org/10.1158/0008-5472.CAN-11-3525