{
  "abstract": "Background\n\nEmerging evidence links neuronal-like phenotypic transition to glioblastoma (GB) recurrence and therapy resistance, yet the underlying mechanisms remain incompletely understood. We hypothesized that dysregulated alternative splicing leads to a neuronal-like state and chemoresistance at tumor recurrence.Methods\n\nWe reanalysed longitudinal bulk RNA-seq data from paired primary and recurrent GBs to quantify dynamic alternative splicing during tumor evolution. By integrating single-cell and spatial transcriptomics, we characterized shifts in cellular composition and spatial interactions linked to these splicing changes. We then prioritized splicing regulators and validated their effects on tumor cells using in vitro cell lines and co-culture assays.Results\n\nA subset of recurrent GBs exhibits neuronal programs and chemoresistance during tumor evolution, accompanied by pronounced differential splicing patterns. Single-cell analyses link these splicing changes to the co-enrichment of neurons and a neuronal-like tumor subpopulation at recurrence. Spatial transcriptomics further indicates close synaptic interactions between this tumor state and adjacent neurons in tumor-infiltrative regions. Through integrative computational ranking and experimental validation, we find that the neuron-specific splicing factor RBFOX3 promotes the neuronal-like GB tumor state by dysregulating splicing. In tumor-neuron co-culture systems, RBFOX3 overexpression is linked to the upregulation of presynaptic markers.Conclusions\n\nDysregulated alternative splicing mediated by RBFOX3 is associated with a neuronal-like tumor state and might contribute to chemoresistance at GB relapse, highlighting the potential role of splicing regulation in GB evolution.",
  "abstract_shown": true,
  "affiliations": [
    "Division of Life Science, Department of Chemical and Biological Engineering, State Key Laboratory of Nervous System Disorders, The Hong Kong University of Science and Technology, Hong Kong SAR, China.",
    "Data Science and Analytics Thrust, The Hong Kong University of Science and Technology (Guangzhou), Nansha, Guangzhou, Guangdong, 511400, China.",
    "Department of Computational Biology, China National Center for Bioinformation, Beijing, China.",
    "Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.",
    "University of Chinese Academy of Sciences, Beijing, China.",
    "Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.",
    "Department of Computational Biology, China National Center for Bioinformation, Beijing, China. liuzq@big.ac.cn.",
    "Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. liuzq@big.ac.cn.",
    "University of Chinese Academy of Sciences, Beijing, China. liuzq@big.ac.cn.",
    "Division of Life Science, Department of Chemical and Biological Engineering, State Key Laboratory of Nervous System Disorders, The Hong Kong University of Science and Technology, Hong Kong SAR, China. jgwang@ust.hk.",
    "Big Data Bio-Intelligence Lab, The Hong Kong University of Science and Technology, Hong Kong, China. jgwang@ust.hk.",
    "SIAT-HKUST Joint Laboratory of Cell Evolution and Digital Health, HKUST Shenzhen-Hong Kong Collaborative Innovation Research Institute, Futian, Shenzhen, 518000, China. jgwang@ust.hk."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 6,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Xiaomeng Zhang"
    },
    {
      "affs": [
        2,
        3,
        4
      ],
      "name": "Jingru Sui"
    },
    {
      "affs": [
        5
      ],
      "name": "Haoyuan Sun"
    },
    {
      "affs": [
        5
      ],
      "name": "Ruichao Chai"
    },
    {
      "affs": [
        6,
        7,
        8
      ],
      "name": "Zhaoqi Liu"
    },
    {
      "affs": [
        9,
        10,
        11
      ],
      "name": "Jiguang Wang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/7w1gbv5v8jmab.bib",
  "cited_by": 0,
  "doi": "10.1186/s12885-026-16597-9",
  "fulltext_url": "https://europepmc.org/articles/PMC13688787",
  "id": "7w1gbv5v8jmab",
  "issns": [
    "1471-2407"
  ],
  "landing_url": "https://europepmc.org/article/MED/42919159",
  "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": [
    [
      "lcc",
      "RC254-282"
    ],
    [
      "openalex",
      "2716|Glioma Diagnosis and Treatment"
    ]
  ],
  "openalex": "W7170874602",
  "pdf_url": "https://europepmc.org/articles/PMC13688787?pdf=render",
  "pmcid": "PMC13688787",
  "pmid": "42919159",
  "published": "2026-07-01",
  "publisher": "BMC",
  "ris": "https://research.draconitic.com/paper/7w1gbv5v8jmab.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:02Z",
      "native_id": "MED:42919159",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42919159"
    },
    {
      "first_seen": "2026-10-30T13:46:06Z",
      "native_id": "dcfbe9ab852c479bba2647546b99a94e",
      "source": "doaj",
      "url": "https://doi.org/10.1186/s12885-026-16597-9"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "openalex:2716|Glioma Diagnosis and Treatment",
      "subfield": "human-genetics"
    }
  ],
  "title": "RBFOX3 is associated with neuronal-like phenotypic transition in recurrent glioblastoma.",
  "title_text": "RBFOX3 is associated with neuronal-like phenotypic transition in recurrent glioblastoma.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T13:46:06Z",
  "url": "https://research.draconitic.com/paper/7w1gbv5v8jmab",
  "venue": "BMC cancer",
  "versions": []
}