GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma

Cell Rep. 2017 Nov 21;21(8):2183-2197. doi: 10.1016/j.celrep.2017.10.083.


A mesenchymal transition occurs both during the natural evolution of glioblastoma (GBM) and in response to therapy. Here, we report that the adhesion G-protein-coupled receptor, GPR56/ADGRG1, inhibits GBM mesenchymal differentiation and radioresistance. GPR56 is enriched in proneural and classical GBMs and is lost during their transition toward a mesenchymal subtype. GPR56 loss of function promotes mesenchymal differentiation and radioresistance of glioma initiating cells both in vitro and in vivo. Accordingly, a low GPR56-associated signature is prognostic of a poor outcome in GBM patients even within non-G-CIMP GBMs. Mechanistically, we reveal GPR56 as an inhibitor of the nuclear factor kappa B (NF-κB) signaling pathway, thereby providing the rationale by which this receptor prevents mesenchymal differentiation and radioresistance. A pan-cancer analysis suggests that GPR56 might be an inhibitor of the mesenchymal transition across multiple tumor types beyond GBM.

Keywords: GPR56; NF-κB; glioblastoma; glioma stem-like initiating cell; mesenchymal differentiation; radioresistance; tumor plasticity.

MeSH terms

  • Brain Neoplasms / metabolism*
  • Cell Differentiation / physiology
  • Cell Line, Tumor
  • Glioblastoma / metabolism*
  • Humans
  • NF-kappa B / metabolism
  • Neoplastic Stem Cells / metabolism*
  • Receptors, G-Protein-Coupled / metabolism*
  • Signal Transduction / physiology


  • ADGRG1 protein, human
  • NF-kappa B
  • Receptors, G-Protein-Coupled