GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma
Marta Moreno 1 , Leire Pedrosa 2 , Laia Paré 3 , Estela Pineda 4 , Leire Bejarano 1 , Josefina Martínez 5 , Veerakumar Balasubramaniyan 6 , Ravesanker Ezhilarasan 7 , Naveen Kallarackal 7 , Sung-Hak Kim 8 , Jia Wang 8 , Alessandra Audia 9 , Siobhan Conroy 10 , Mercedes Marin 3 , Teresa Ribalta 11 , Teresa Pujol 12 , Antoni Herreros 13 , Avelina Tortosa 5 , Helena Mira 14 , Marta M Alonso 15 , Candelaria Gómez-Manzano 6 , Francesc Graus 16 , Erik P Sulman 7 , Xianhua Piao 17 , Ichiro Nakano 8 , Aleix Prat 18 , Krishna P Bhat 9 , Núria de la Iglesia 19
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.
CITA DEL ARTÍCULO Cell Rep. 2017 Nov 21;21(8):2183-2197. doi: 10.1016/j.celrep.2017.10.083