{
  "abstract": "Background Anti-vascular endothelial growth factor (VEGF) therapies are central to the treatment of advanced hepatocellular carcinoma (HCC), yet clinical benefit is often limited by adaptive resistance. Vasculogenic mimicry (VM), a VEGF-independent vascularisation strategy driven by tumour cells, is associated with aggressive disease, but its regulatory mechanisms remain poorly defined. Cytoplasmic polyadenylation element binding protein 4 (CPEB4) is a translational regulator implicated in liver stress adaptation and hepatocarcinogenesis, and reduced CPEB4 expression has been associated with aggressive HCC and poor outcome. However, its role in tumour vascular plasticity is unknown.Objective To determine whether CPEB4 restrains VM and tumour adaptation to VEGF blockade in HCC.Design We combined human and murine liver cancer models with genetic CPEB4 loss, xenografts, transcriptomic and ribosome profiling analyses and functional vascular assays.Results CPEB4 loss enhanced tumour cell-intrinsic VM capacity and promoted formation of VM structures in vivo. CPEB4-deficient tumours displayed vascular remodelling with preservation of VM channels and endothelial vessels together with reduced hypoxia, apoptosis and necrosis. Under VEGF blockade, endothelial networks were impaired whereas VM activity persisted; notably, CPEB4-deficient tumour cells sustained vascular network organisation and tumour viability. Mechanistically, CPEB4 loss induced an epithelial-to-mesenchymal transition (EMT)-associated plasticity programme and enrichment of EMT-related signatures at the translational level, including increased ribosome occupancy of EMT-associated transcripts. Consistent with this, EMT regulators were enriched for cytoplasmic polyadenylation elements, suggesting post-transcriptional control.Conclusions CPEB4 acts as a tumour cell-intrinsic suppressor of VM in HCC. Its loss promotes an EMT-associated adaptive programme that reduces reliance on VEGF-driven angiogenesis and supports a mechanism of adaptive resistance to anti-angiogenic therapy.",
  "authors": [
    {
      "affiliations": [
        "Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"
      ],
      "name": "Beatriz I Cárdenas"
    },
    {
      "affiliations": [
        "Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"
      ],
      "name": "Salvador Naranjo Suarez"
    },
    {
      "affiliations": [
        "Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"
      ],
      "name": "Isabel Baroja"
    },
    {
      "affiliations": [
        "School of Medicine, University of Navarra, Pamplona, Spain"
      ],
      "name": "Ana Mendez"
    },
    {
      "affiliations": [
        "Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"
      ],
      "name": "Pau Bosch-i-Crespo"
    },
    {
      "affiliations": [
        "Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"
      ],
      "name": "Carmen Gallardo-Martínez"
    },
    {
      "affiliations": [
        "Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"
      ],
      "name": "Marta Ramirez-Pedraza"
    },
    {
      "affiliations": [
        "Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain"
      ],
      "name": "M. Eugenia Delgado"
    },
    {
      "affiliations": [
        "Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain",
        "Universitat Internacional de Catalunya, Sant Cugat del Valles, Spain"
      ],
      "name": "Laura Morató"
    },
    {
      "affiliations": [
        "Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain"
      ],
      "name": "Eulalia Belloc"
    },
    {
      "affiliations": [
        "Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain"
      ],
      "name": "Judit Martin"
    },
    {
      "affiliations": [
        "Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain"
      ],
      "name": "Alba Millanes-Romero"
    },
    {
      "affiliations": [
        "Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain",
        "Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain"
      ],
      "name": "Raul Mendez"
    },
    {
      "affiliations": [
        "Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain",
        "Universitat Internacional de Catalunya, Sant Cugat del Valles, Spain",
        "Universitat de Barcelona (UB), Barcelona, Spain"
      ],
      "name": "Mercedes Fernandez"
    }
  ],
  "title": "CPEB4 deficiency promotes vasculogenic mimicry and resistance to anti-angiogenic therapy in hepatocellular carcinoma",
  "uid": "e9ea5a49-0218-5fec-bc00-c61467135cd5"
}