Affiliations 

  • 1 Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA
  • 2 Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA; Neuroscience Program, Harvard Medical School, Boston, MA 02129, USA
  • 3 Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA; Department of Human Anatomy, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, Seri Kembangan, Selangor 43400, Malaysia
  • 4 Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
  • 5 Department of Neurology, Massachusetts General Hospital, Boston, MA 02129, USA; Neuroscience Program, Harvard Medical School, Boston, MA 02129, USA. Electronic address: badr.christian@mgh.harvard.edu
Stem Cell Reports, 2019 04 09;12(4):712-727.
PMID: 30930246 DOI: 10.1016/j.stemcr.2019.02.012

Abstract

Inherent plasticity and various survival cues allow glioblastoma stem-like cells (GSCs) to survive and proliferate under intrinsic and extrinsic stress conditions. Here, we report that GSCs depend on the adaptive activation of ER stress and subsequent activation of lipogenesis and particularly stearoyl CoA desaturase (SCD1), which promotes ER homeostasis, cytoprotection, and tumor initiation. Pharmacological targeting of SCD1 is particularly toxic due to the accumulation of saturated fatty acids, which exacerbates ER stress, triggers apoptosis, impairs RAD51-mediated DNA repair, and achieves a remarkable therapeutic outcome with 25%-100% cure rate in xenograft mouse models. Mechanistically, divergent cell fates under varying levels of ER stress are primarily controlled by the ER sensor IRE1, which either promotes SCD1 transcriptional activation or converts to apoptotic signaling when SCD1 activity is impaired. Taken together, the dependence of GSCs on fatty acid desaturation presents an exploitable vulnerability to target glioblastoma.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.