Ruolun Wei ^1,2 Haoyun Xie ³ Yukun Zhou ⁴ Xuhao Chen ⁵ Liwei Zhang ⁶ Brandon Bui ^7,8 Liu Xianzhi ^1*

• ¹ Department of Neurosurgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
• ² Department of Neurosurgery, Stanford University, Stanford, United States
• ³ Biochemistry and Molecular Biology, Georgetown University, Washington, District of Columbia, United States
• ⁴ Department of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei Province, China
• ⁵ Department of Pathophysiology, School of Medicine, Zhengzhou University, Zhengzhou, Henan Province, China
• ⁶ Department of Vascular Surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China
• ⁷ Department of Neurosurgery, School of Medicine, Stanford University, Stanford, California, United States
• ⁸ Department of Human Biology, Stanford University, Stanford, California, United States

Gliomas, the most prevalent primary malignant intracranial tumors, are characterized by high rates of therapy resistance, recurrence rate, and mortality. A major factor contributing to the poor prognosis of gliomas is that glioma cell is capable of diffusely infiltrate into surrounding and even distance brain tissues, making complete total resection almost impossible, and leading to frequent recurrence. The extracellular matrix (ECM) is the key factor in tumor microenvironment, may significantly influencing glioma progression, recurrence, and therapeutic response. In this study, we firstly 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. Then by single-cell sequencing, we revealed heterogeneous distribution patterns and extensive intercellular communication of ECM components. External sequencing and immunohistochemical (IHC) staining furtherly validated that VCAN is significantly upregulated in recurrent gliomas and is associated with poor patient outcomes. Functional assays 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. These findings provide valuable insights into the mechanisms of glioma recurrence and suggest that targeting both VCAN and the PI3K/Akt pathway could represent a promising therapeutic strategy for managing recurrent gliomas.