Li Yi, Shuhang Qin, Min Guo, Xuya Wang, Yiming Zhang, Peiquan Guo, Arne Östman, Xuejun Yang, Xiaobing Jiang
Our study demonstrates that PTPRZ1 drives glioblastoma migration by sustaining an OPA1-dependent mitochondrial fusion program, which suppresses mitochondrial ROS levels and subsequently stabilizes a pro-migratory phenotype via N-cadherin expression. Targeting the PTPRZ1/OPA1/ROS axis represents a promising therapeutic strategy to inhibit the invasive expansion of GBM cells.
BACKGROUND: Glioblastoma (GBM) is characterized by high invasiveness and metabolic heterogeneity. Protein Tyrosine Phosphatase Receptor Type Z1 (PTPRZ1) has been implicated in glioma stemness and tumor grade progression, while the molecular mechanism remains unknown.
METHODS: Integrated bioinformatics analysis of TCGA dataset and TMA IHC profiling were used to explore clinical relevance of PTPRZ1, and potential molecular mechanisms of PTPRZ1 involved glioma progression. Ivy Glioblastoma datasets analysis and multiregional GBM IHC were performed to spatially characterize the expression patterns of PTPRZ1 in GBM tissues. Zebrafish xenograft model was established to elucidate the role of PTPRZ1 in driving glioblastoma cell migration. Western blotting, mitochondrial functional assays, Transwell migration assays, and human GBM tissue multiplexing were employed to investigate the mechanism of PTPRZ1 mediated glioma cell mobility via maintaining mitochondrial functions.
RESULTS: Spatial profiling revealed that PTPRZ1 is significantly enriched in the infiltrating areas and peritumoral margins of GBM, and acts as a poor prognosis factor in lower grade astrocytoma, proneural and mesenchymal GBM. Mechanistically, PTPRZ1 expression was found to be strongly correlated with cell adhesion molecules (CAMs) and mitochondrial metabolism across multiple glioma subtypes. Knockdown of PTPRZ1 triggered a shift from elongated to fragmented mitochondrial morphology by specifically downregulating the mitochondrial fusion protein OPA1. This mitochondrial dysfunction led to a metabolic shift toward glycolysis and a marked accumulation of ROS, which suppressed N-cadherin expression, thereby impairing glioma cell migration. These findings were corroborated in vivo, where PTPRZ1 depletion significantly reduced disseminated tumor foci in a zebrafish model.
CONCLUSION: Our study demonstrates that PTPRZ1 drives glioblastoma migration by sustaining an OPA1-dependent mitochondrial fusion program, which suppresses mitochondrial ROS levels and subsequently stabilizes a pro-migratory phenotype via N-cadherin expression. Targeting the PTPRZ1/OPA1/ROS axis represents a promising therapeutic strategy to inhibit the invasive expansion of GBM cells.