VCAN in the extracellular matrix drives glioma recurrence by enhancing cell proliferation and migration.

Introduction: Gliomas are the most prevalent primary malignant intracranial tumors, characterized by high rates of therapy resistance, recurrence, and mortality. A major factor contributing to the poor prognosis of gliomas is their ability to diffusely infiltrate surrounding and even distant brain tissues, rendering complete total resection almost impossible and leading to frequent recurrences. The extracellular matrix (ECM) plays a key role in the tumor microenvironment and may significantly influence glioma progression, recurrence, and therapeutic response. Methods: In this study, we first identified the ECM and the Versican (VCAN), a key ECM protein, as critical contributors to glioma recurrence through a comprehensive analysis of transcriptomic data comparing recurrent and primary gliomas. Using single-cell sequencing, we revealed heterogeneous distribution patterns and extensive intercellular communication among ECM components. External sequencing and immunohistochemical (IHC) staining further validated that VCAN is significantly upregulated in recurrent gliomas and is associated with poor patient outcomes. Results: Functional assays conducted in glioma cell lines overexpressing VCAN demonstrated that VCAN promotes cell proliferation and migration via the PI3K/Akt/AP-1 signaling pathway. Furthermore, inhibiting the PI3K/Akt pathway effectively blocked VCAN-mediated glioma progression. Conclusion: These findings provide valuable insights into the mechanisms underlying glioma recurrence and suggest that targeting both VCAN and the PI3K/Akt pathway could represent a promising therapeutic strategy for managing recurrent gliomas.