Glioma and Neural Stem Cell Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
Glioma and Neural Stem Cell Group, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain; Translational Genomics and Targeted Therapeutics in Solid Tumors Team, August Pi i Sunyer Biomedical Research Institute (IDIBAPS), Barcelona, Spain.
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.
间质转化既发生在胶质母细胞瘤（GBM）的自然演变过程中，也发生在对治疗的反应中。在这里，我们报告说，黏附 G 蛋白偶联受体 GPR56/ADGRG1 抑制 GBM 间质分化和放射抵抗。GPR56 在神经前体细胞型和经典型 GBM 中富集，并在向间质亚型转化过程中丢失。GPR56 功能丧失促进胶质瘤起始细胞在体外和体内的间质分化和放射抵抗。因此，即使在非 G-CIMP GBM 中，低 GPR56 相关特征也预示着 GBM 患者预后不良。从机制上讲，我们揭示了 GPR56 作为核因子 kappa B (NF-κB) 信号通路的抑制剂，从而为该受体阻止间质分化和放射抵抗提供了依据。泛癌分析表明，GPR56 可能是多种肿瘤类型（GBM 以外）间质转化的抑制剂。
