GPR56/ADGRG1 Inhibits Mesenchymal Differentiation and Radioresistance in Glioblastoma

Marta Moreno, Leire Pedrosa, Laia Pare, Estela Pineda, Leire Bejarano, Josefina Martinez, 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. AlonsoCandelaria Gomez-Manzano, Francesc Graus, Erik P. Sulman, Xianhua Piao, Ichiro Nakano, Aleix Prat, Krishna P. Bhat, Nuria de la Iglesia*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    27 Citations (Scopus)
    258 Downloads (Pure)

    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 classicalGBMs 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-kappa B) 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.

    Original languageEnglish
    Pages (from-to)2183-2197
    Number of pages15
    JournalCell reports
    Volume21
    Issue number8
    DOIs
    Publication statusPublished - 21-Nov-2017

    Keywords

    • PROTEIN-COUPLED RECEPTOR
    • INTEGRATED GENOMIC ANALYSIS
    • NF-KAPPA-B
    • BREAST-CANCER
    • RADIATION RESPONSE
    • GENE-EXPRESSION
    • STEM-CELLS
    • MALIGNANT GLIOMA
    • GROWTH-FACTOR
    • RNA-SEQ

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