{
  "abstract": "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. We integrated single-cell RNA sequencing (scRNA-seq) datasets across four independent cohorts (including GRTI-Atlas, Jackson et al., Mei et al., and Abdelfattah et al.) 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. Multi-omics integration identified 13 core malignant hub genes, among which PDIA6 emerged as the top regulator exhibiting tight, consistent spatial colocalization with EC-high niches. Multi-scale profiling, pan-cancer dependency screens, and tissue validations confirmed that cytoplasmic PDIA6 was upregulated in high-grade GBM, particularly within proliferating MKI67 and mesenchymal-like (MES_like_3.CD44) cell states. Mechanistically, PDIA6 expression strongly correlated with aggressive stress adaptation programs, including the unfolded protein response (UPR) and mTORC1 signaling, while suppressing T-cell-mediated cytotoxicity. Crucially, high PDIA6 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. Our study identified PDIA6 as a pivotal tumor-derived orchestrator of the vascular microenvironment in GBM. By driving mesenchymal plasticity, metabolic stress adaptation, and immune evasion within perivascular niches, PDIA6 represented a promising therapeutic target to dismantle the protective vascular sanctuary and overcome microenvironmental resistance in GBM.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Neurosurgery & Brain and Nerve Research Laboratory, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China.",
    "Department of Neurosurgery, Suzhou Ninth Hospital Affiliated to Soochow University, Soochow University, Suzhou, China."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Changyang Zuo"
    },
    {
      "affs": [
        0
      ],
      "name": "Guozheng Zhao"
    },
    {
      "affs": [
        1
      ],
      "name": "Jie Lu"
    },
    {
      "affs": [
        1
      ],
      "name": "Junwei Ren"
    },
    {
      "affs": [
        1
      ],
      "name": "Yangqing Zhu"
    },
    {
      "affs": [
        0
      ],
      "name": "Xin Wu"
    },
    {
      "affs": [
        0
      ],
      "name": "Zhengquan Yu"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/d6txfvbvgxg3s.bib",
  "cited_by": 0,
  "doi": "10.21037/tcr-2026-2106",
  "fulltext_url": "https://europepmc.org/articles/PMC13743201",
  "id": "d6txfvbvgxg3s",
  "issns": [
    "2218-676X",
    "2219-6803"
  ],
  "landing_url": "https://europepmc.org/article/MED/42997716",
  "language": "eng",
  "licence": "CC-BY-NC-ND",
  "licence_label": "CC BY-NC-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "heading",
      "Original Article"
    ],
    [
      "openalex",
      "2730|Glioma Diagnosis and Treatment"
    ]
  ],
  "openalex": "W7223290653",
  "pdf_url": "https://europepmc.org/articles/PMC13743201?pdf=render",
  "pmcid": "PMC13743201",
  "pmid": "42997716",
  "published": "2026-09-28",
  "publisher": "AME Publications",
  "ris": "https://research.draconitic.com/paper/d6txfvbvgxg3s.ris",
  "sources": [
    {
      "first_seen": "2026-11-09T15:20:41Z",
      "native_id": "MED:42997716",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42997716"
    },
    {
      "first_seen": "2026-11-10T12:23:54Z",
      "native_id": "PMC13743201",
      "source": "pmc",
      "url": "https://doi.org/10.21037/tcr-2026-2106"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Glioma Diagnosis and Treatment",
      "subfield": "oncology"
    }
  ],
  "title": "Spatial transcriptomics reveals PDIA6 as a tumor-intrinsic driver of mesenchymal plasticity and vascular microenvironment remodeling in glioblastoma.",
  "title_text": "Spatial transcriptomics reveals PDIA6 as a tumor-intrinsic driver of mesenchymal plasticity and vascular microenvironment remodeling in glioblastoma.",
  "type": "peer-reviewed",
  "updated_at": "2026-11-10T12:23:54Z",
  "url": "https://research.draconitic.com/paper/d6txfvbvgxg3s",
  "venue": "Translational cancer research",
  "versions": []
}