Cell Reports (Nov 2017)
GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma
- Marta Moreno,
- Leire Pedrosa,
- Laia Paré,
- Estela Pineda,
- Leire Bejarano,
- Josefina Martínez,
- Veerakumar Balasubramaniyan,
- Ravesanker Ezhilarasan,
- Naveen Kallarackal,
- Sung-Hak Kim,
- Jia Wang,
- Alessandra Audia,
- Siobhan Conroy,
- Mercedes Marin,
- Teresa Ribalta,
- Teresa Pujol,
- Antoni Herreros,
- Avelina Tortosa,
- Helena Mira,
- Marta M. Alonso,
- Candelaria Gómez-Manzano,
- Francesc Graus,
- Erik P. Sulman,
- Xianhua Piao,
- Ichiro Nakano,
- Aleix Prat,
- Krishna P. Bhat,
- Núria de la Iglesia
Affiliations
- Marta Moreno
- Glioma and Neural Stem Cell Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Leire Pedrosa
- Glioma and Neural Stem Cell Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Laia Paré
- Translational Genomics and Targeted Therapeutics in Solid Tumors Team, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Estela Pineda
- Translational Genomics and Targeted Therapeutics in Solid Tumors Team, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Leire Bejarano
- Glioma and Neural Stem Cell Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Josefina Martínez
- Department of Basic Nursing, Universitat de Barcelona-Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
- Veerakumar Balasubramaniyan
- Department of Neuro-Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA
- Ravesanker Ezhilarasan
- Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA
- Naveen Kallarackal
- Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA
- Sung-Hak Kim
- Department of Neurosurgery, Comprehensive Cancer Center, University of Alabama at Birmingham, AL 35233, USA
- Jia Wang
- Department of Neurosurgery, Comprehensive Cancer Center, University of Alabama at Birmingham, AL 35233, USA
- Alessandra Audia
- Department of Translational Molecular Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA
- Siobhan Conroy
- Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, the Netherlands
- Mercedes Marin
- Translational Genomics and Targeted Therapeutics in Solid Tumors Team, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Teresa Ribalta
- Department of Pathology, Hospital Clinic, Barcelona, Spain
- Teresa Pujol
- Department of Radiology, Hospital Clinic, Barcelona, Spain
- Antoni Herreros
- Department of Radiation Oncology, Hospital Clinic, Barcelona, Spain
- Avelina Tortosa
- Department of Basic Nursing, Universitat de Barcelona-Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), Barcelona, Spain
- Helena Mira
- Stem Cells and Aging Unit, Biomedicine Institute of València (IBV), Spanish National Research Council (CSIC), València, Spain
- Marta M. Alonso
- Department of Pediatrics, University Hospital of Navarra, Pamplona, Navarra, Spain
- Candelaria Gómez-Manzano
- Department of Neuro-Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA
- Francesc Graus
- Clinical and Experimental Neuroimmunology, IDIBAPS, Barcelona, Spain
- Erik P. Sulman
- Department of Radiation Oncology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA
- Xianhua Piao
- Division of Newborn Medicine, Department of Medicine, Boston Children’s Hospital and Harvard Medical School, Boston, MA 02115, USA
- Ichiro Nakano
- Department of Neurosurgery, Comprehensive Cancer Center, University of Alabama at Birmingham, AL 35233, USA
- Aleix Prat
- Glioma and Neural Stem Cell Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- Krishna P. Bhat
- Department of Translational Molecular Pathology, The University of Texas, M.D. Anderson Cancer Center, Houston, TX 77030, USA
- Núria de la Iglesia
- Glioma and Neural Stem Cell Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain
- DOI
- https://doi.org/10.1016/j.celrep.2017.10.083
- Journal volume & issue
-
Vol. 21,
no. 8
pp. 2183 – 2197
Abstract
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
- glioblastoma
- mesenchymal differentiation
- radioresistance
- NF-κB
- glioma stem-like initiating cell
- tumor plasticity
