Neovascularization directed by CAVIN1/CCBE1/VEGFC confers TMZ-resistance in glioblastoma

Abstract

Acquisition of resistance to temozolomide (TMZ) poses a significant challenge in glioblastoma (GBM) therapy. Neovascularization, a pivotal process in tumorigenesis and development, remains poorly understood in its contribution to chemoresistance in GBMs. This study unveils aberrant vascular networks within TMZ-resistant (TMZ-R) GBM tissues and identifies the extracellular matrix (ECM) protein CCBE1 as a potential mediator. Through in vivo and in vitro experiments involving gain and loss of function assessments, we demonstrate that high expression of CCBE1 promotes hyper-angiogenesis and orchestrates partial endothelial-to-mesenchymal transition (EndMT) in human microvascular endothelial cells (HCMEC/d3) within GBM. This is likely driven by VEGFC/Rho signaling. Intriguingly, CCBE1 overexpression substantially fails to promote tumor growth, but endows resistance to GBM cells in a vascular endothelial cell-dependent manner. Mechanically, the constitutive phosphorylation of SP1 at Ser101 drives the upregulation of CCBE1 transcription in TMZ resistant tumors, and the excretion of CCBE1 depends on caveolae associated protein 1 (CAVIN1) binding and assembling. Tumor cells derived CCBE1 promotes VEGFC maturation, activates VEGFR2/VEGFR3/Rho signaling in vascular endothelial cells, and ultimately results in hyper-angiogenesis in TMZ-R tumors. Collectively, the current study uncovers the cellular and molecular basis of abnormal angiogenesis in a chemo resistant microenvironment, implying that curbing CCBE1 is key to reversing TMZ resistance.