Spatial transcriptomics reveals PDIA6 as a tumor-intrinsic driver of mesenchymal plasticity and vascular microenvironment remodeling in glioblastoma
Year: 2026
Type: article
Abstract: Background: Glioblastoma (GBM) is characterized by pronounced microenvironmental heterogeneity, severe hypoxia, and profound resistance to conventional and targeted therapies. While abnormal tumor angiogenesis and perivascular niches are recognized hallmarks of GBM, the tumor-intrinsic drivers that actively orchestrate malignant-endothelial crosstalk and structure protective vascular sanctuaries remain to be fully defined. To identify key tumor-intrinsic vascular orchestrators, this study focused on PDIA6 and investigated its functional role and clinical significance in GBM mesenchymal plasticity, malignant proliferation, and microenvironmental remodeling using single-cell virtual knockout modeling and multi-cohort transcriptomic validation. Methods: ) to establish conserved endothelial lineage signatures [Tip-like, Cap, Vein, and Arterial endothelial cells (ECs)]. By applying MOVICS (multi-omics integration and visualization in cancer subtyping) based on these endothelial signatures, we established two molecularly distinct patient subtypes (CS1 and CS2). To isolate tumor-intrinsic vascular hubs, we executed an integrative screening strategy combining CS2-upregulated genes, prognostic meta-analysis risk genes across seven bulk cohorts (n=890), and conserved malignant markers, followed by spatial deconvolution across 50 patient-derived Visium spatial transcriptomics (ST) sections to validate physical proximity within endothelial-high (EC-high) spots. Results: expression served as an independent risk factor for poor overall survival and predicted non-response to immune checkpoint blockade (ICB) and combination therapies in clinical settings. Conclusions: represented a promising therapeutic target to dismantle the protective vascular sanctuary and overcome microenvironmental resistance in GBM.
Source: Translational Cancer Research
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: diamond
OpenAlex ID: W7223290653