GPR133 (ADGRD1), an adhesion G-protein-coupled receptor, is necessary for glioblastoma growth

Oncogenesis. 2016 Oct 24;5(10):e263. doi: 10.1038/oncsis.2016.63.

N S Bayin ¹ ², J D Frenster ¹ ², J R Kane ¹, J Rubenstein ¹, A S Modrek ¹, R Baitalmal ³, I Dolgalev ⁴, K Rudzenski ⁵, L Scarabottolo ⁶, D Crespi ⁶, L Redaelli ⁶, M Snuderl ³ ⁷ ⁸, J G Golfinos ¹ ⁷ ⁸, W Doyle ¹, D Pacione ¹, E C Parker ¹, A S Chi ⁷ ⁸ ⁹, A Heguy ⁴, D J MacNeil ⁵, N Shohdy ⁵, D Zagzag ¹ ³ ⁷ ⁸, D G Placantonakis ¹ ² ⁷ ⁸

Affiliations

1 Department of Neurosurgery, New York University School of Medicine, New York, NY, USA.
2 Kimmel Center for Stem Cell Biology, New York University School of Medicine, New York, NY, USA.
3 Department of Pathology, New York University School of Medicine, New York, NY, USA.
4 Genome Technology Center, New York University School of Medicine, New York, NY, USA.
5 Office for Therapeutic Alliances, New York University School of Medicine, New York, NY, USA.
6 Axxam SpA, Milan, Italy.
7 Brain Tumor Center, New York University School of Medicine, New York, NY, USA.
8 Perlmutter Cancer Center, New York University School of Medicine, New York, NY, USA.
9 Department of Neurology, New York University School of Medicine, New York, NY, USA.

PMID: 27775701 DOI: 10.1038/oncsis.2016.63

Abstract

Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM. GPR133 is selectively expressed in CD133+ GBM stem cells (GSCs) and within the hypoxic areas of PPN in human biospecimens. GPR133 mRNA is transcriptionally upregulated by hypoxia in hypoxia-inducible factor 1α (Hif1α)-dependent manner. Genetic inhibition of GPR133 with short hairpin RNA reduces the prevalence of CD133+ GSCs, tumor cell proliferation and tumorsphere formation in vitro. Forskolin rescues the GPR133 knockdown phenotype, suggesting that GPR133 signaling is mediated by cAMP. Implantation of GBM cells with short hairpin RNA-mediated knockdown of GPR133 in the mouse brain markedly reduces tumor xenograft formation and increases host survival. Analysis of the TCGA data shows that GPR133 expression levels are inversely correlated with patient survival. These findings indicate that GPR133 is an important mediator of the hypoxic response in GBM and has significant protumorigenic functions. We propose that GPR133 represents a novel molecular target in GBM and possibly other malignancies where hypoxia is fundamental to pathogenesis.

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