The expression profile and tumorigenic mechanisms of CD97 (ADGRE5) in glioblastoma render it a targetable...

Area of Science:

• Neuro-oncology
• Molecular biology
• Cell signaling

Background:

• Glioblastoma (GBM) is a highly aggressive primary brain tumor.
• Adhesion G protein-coupled receptors (aGPCRs) are emerging as potential therapeutic targets in oncology.
• CD97 (ADGRE5) exhibits de novo expression in GBM compared to healthy brain tissue.

Purpose of the Study:

• To investigate CD97 (ADGRE5) as a therapeutic target in glioblastoma (GBM).
• To elucidate the role of CD97 in GBM tumor initiation, metabolism, and signaling pathways.
• To evaluate the therapeutic potential of targeting CD97 in GBM.

Main Methods:

• Utilized patient-derived GBM cultures (PDGCs) for in vitro and in vivo studies.
• Performed CD97 knockdown and knockout experiments.
• Investigated the mitogen-activated protein kinase (MAPK) pathway and β-arrestin recruitment.
• Identified THY1/CD90 as a potential CD97 ligand.
• Tested an anti-CD97 antibody-drug conjugate for selective tumor cell killing.

Main Results:

• CD97 knockdown/knockout significantly reduced GBM tumor initiation capacity.
• CD97 promotes GBM glycolytic metabolism via the MAPK pathway, dependent on C-terminal phosphorylation and β-arrestin.
• THY1/CD90 was identified as a likely CD97 ligand in GBM.
• An anti-CD97 antibody-drug conjugate demonstrated selective killing of GBM cells in vitro.

Conclusions:

• CD97 (ADGRE5) is a critical regulator of tumor metabolism in GBM.
• Understanding CD97 activation and signaling provides mechanistic insights.
• These findings provide a strong rationale for developing biologics targeting CD97 for GBM therapy.