胶质母细胞瘤（GBM）是最常见和最具侵袭性的原发性脑恶性肿瘤。粘附 G 蛋白偶联受体 (aGPCR) 因其作为治疗靶点的潜力而引起了人们的兴趣。在这里，我们证明 CD97 (ADGRE5) 是 GBM 中最有前途的 aGPCR 靶点，因为与健康脑组织相比，它的从头表达。 CD97 敲低或基因敲除显着降低了体外和体内患者来源的 GBM 培养物 (PDGC) 的肿瘤起始能力。我们发现 CD97 通过丝裂原激活蛋白激酶 (MAPK) 途径促进糖酵解代谢，该途径依赖于其 C 末端的磷酸化和 β-arrestin 的募集。我们还证明 THY1/CD90 可能是 GBM 中的 CD97 配体。最后，我们证明抗 CD97 抗体-药物偶联物可以在体外选择性杀死肿瘤细胞。我们的研究确定 CD97 是肿瘤代谢的调节剂，阐明了受体激活和信号转导的机制，并为开发 GBM 中靶向治疗的生物制剂提供了强有力的科学依据。版权所有 © 2023 作者。由爱思唯尔公司出版。保留所有权利。

Glioblastoma (GBM) is the most common and aggressive primary brain malignancy. Adhesion G protein-coupled receptors (aGPCRs) have attracted interest for their potential as treatment targets. Here, we show that CD97 (ADGRE5) is the most promising aGPCR target in GBM, by virtue of its de novo expression compared to healthy brain tissue. CD97 knockdown or knockout significantly reduces the tumor initiation capacity of patient-derived GBM cultures (PDGCs) in vitro and in vivo. We find that CD97 promotes glycolytic metabolism via the mitogen-activated protein kinase (MAPK) pathway, which depends on phosphorylation of its C terminus and recruitment of β-arrestin. We also demonstrate that THY1/CD90 is a likely CD97 ligand in GBM. Lastly, we show that an anti-CD97 antibody-drug conjugate selectively kills tumor cells in vitro. Our studies identify CD97 as a regulator of tumor metabolism, elucidate mechanisms of receptor activation and signaling, and provide strong scientific rationale for developing biologics to target it therapeutically in GBM.Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.