{
  "abstract": "Vascular invasion (VascI) is a critical step in colorectal cancer (CRC) metastasis, but how specific cells in the tumor microenvironment (TME) regulate this process remains unclear, particularly the role of endothelial cells (ECs). Here, we found that vascular invasion is strongly associated with distant metastasis and poor prognosis in CRC patients. Analysis of single-cell RNA sequencing (scRNA-seq) data from 8 colorectal cancer liver metastases (CRLMs), included 4 VascI⁺ CRLMs and 4 VascI⁻ CRLMs, and identified 10 distinct EC subpopulations. Notably, an IGFBP5_tipECs significantly enriched in VascI⁺ CRLMs. High IGFBP5 expression correlated with VascI⁺ status and poor patient prognosis. Functionally, IGFBP5 overexpression (OE) in human umbilical vein endothelial cells (HUVECs) enhanced EC migration, tube formation, barrier disruption, and endothelial-to-mesenchymal transition (EndMT). In co-culture system, IGFBP5-OE ECs promoted malignant epithelial cells (MCs) proliferation, migration, and adhesion, and accelerated the growth of patient-derived CRC organoids. Mechanistically, RNA sequencing nominated ITGB3 as a key downstream effector, with activation of the PI3K/AKT signaling pathway. We confirmed a direct ligand-receptor interaction between EC-derived IGFBP5 and ITGB3 on MCs using multiplex immunofluorescence (mIF), co-immunoprecipitation (Co-IP), and proximity ligation assays (PLA). This interaction activated PI3K/AKT signaling in MCs, driving aggressive behavior both in vitro and in vivo, an effect that was significantly attenuated by ITGB3 silencing in MCs. Our findings identify IGFBP5-OE ECs as a key driver of VascI and liver metastasis in CRC via the ITGB3/PI3K/AKT axis, highlighting a potential therapeutic target to suppress metastatic progression.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.",
    "Department of Pathology, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.",
    "Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. chenxiao9131@hotmail.com.",
    "Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. purage@163.com.",
    "Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. zhaohong@cicams.ac.cn.",
    "Department of Hepatobiliary Surgery, State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. caijianqiang@cicams.ac.cn."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 11,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Nuersimanguli Maimaitiming"
    },
    {
      "affs": [
        0
      ],
      "name": "Yiqiao Deng"
    },
    {
      "affs": [
        0
      ],
      "name": "Huayuan Liu"
    },
    {
      "affs": [
        0
      ],
      "name": "Junshuai Xue"
    },
    {
      "affs": [
        0
      ],
      "name": "Chengyao Guo"
    },
    {
      "affs": [
        0
      ],
      "name": "Xiaomeng Liu"
    },
    {
      "affs": [
        1
      ],
      "name": "Bingzhi Wang"
    },
    {
      "affs": [
        2
      ],
      "name": "Xiao Chen",
      "orcid": "0009-0002-1516-2806"
    },
    {
      "affs": [
        3
      ],
      "name": "Zhen Huang"
    },
    {
      "affs": [
        4
      ],
      "name": "Hong Zhao",
      "orcid": "0000-0003-0323-5190"
    },
    {
      "affs": [
        5
      ],
      "name": "Jianqiang Cai",
      "orcid": "0000-0002-3426-4579"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/865kp8sr44hqd.bib",
  "cited_by": 0,
  "doi": "10.1038/s41419-026-09081-6",
  "fulltext_url": "https://europepmc.org/articles/PMC13680512",
  "id": "865kp8sr44hqd",
  "issns": [
    "2041-4889"
  ],
  "landing_url": "https://europepmc.org/article/MED/42897140",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "lcc",
      "QH573-671"
    ],
    [
      "openalex",
      "2730|Cancer Cells and Metastasis"
    ]
  ],
  "openalex": "W7170171226",
  "pdf_url": "https://europepmc.org/articles/PMC13680512?pdf=render",
  "pmcid": "PMC13680512",
  "pmid": "42897140",
  "published": "2026-07-01",
  "publisher": "Nature Publishing Group",
  "ris": "https://research.draconitic.com/paper/865kp8sr44hqd.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:42Z",
      "native_id": "MED:42897140",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42897140"
    },
    {
      "first_seen": "2026-10-30T13:46:32Z",
      "native_id": "45e0d915d3354bfebcfe322a238609a2",
      "source": "doaj",
      "url": "https://doi.org/10.1038/s41419-026-09081-6"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2730|Cancer Cells and Metastasis",
      "subfield": "oncology"
    }
  ],
  "title": "IGFBP5 derived from endothelial cells drive vascular invasion and liver metastasis of colorectal cancer by activating the ITGB3/PI3K/AKT Axis.",
  "title_text": "IGFBP5 derived from endothelial cells drive vascular invasion and liver metastasis of colorectal cancer by activating the ITGB3/PI3K/AKT Axis.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:46:32Z",
  "url": "https://research.draconitic.com/paper/865kp8sr44hqd",
  "venue": "Cell death & disease",
  "versions": []
}