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Peer-reviewedCC BY-NC-NDBMC cancer

RBFOX3 is associated with neuronal-like phenotypic transition in recurrent glioblastoma.

  • Xiaomeng Zhang1,2
  • Jingru Sui3,4,5
  • Haoyuan Sun6
  • Ruichao Chai6
  • Zhaoqi Liu7,8,9
  • Jiguang Wang10,11,12
12 affiliations
  1. 1Division 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.
  2. 2Data Science and Analytics Thrust, The Hong Kong University of Science and Technology (Guangzhou), Nansha, Guangzhou, Guangdong, 511400, China.
  3. 3Department of Computational Biology, China National Center for Bioinformation, Beijing, China.
  4. 4Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China.
  5. 5University of Chinese Academy of Sciences, Beijing, China.
  6. 6Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
  7. 7Department of Computational Biology, China National Center for Bioinformation, Beijing, China. [email protected].
  8. 8Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China. [email protected].
  9. 9University of Chinese Academy of Sciences, Beijing, China. [email protected].
  10. 10Division 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. [email protected].
  11. 11Big Data Bio-Intelligence Lab, The Hong Kong University of Science and Technology, Hong Kong, China. [email protected].
  12. 12SIAT-HKUST Joint Laboratory of Cell Evolution and Digital Health, HKUST Shenzhen-Hong Kong Collaborative Innovation Research Institute, Futian, Shenzhen, 518000, China. [email protected].
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Abstract

Background

Emerging 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

We 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

A 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

Dysregulated 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.

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Cite

BibTeXRIS
BibTeX
@article{zhang2026rbfox3,
  title = {{RBFOX3 is associated with neuronal-like phenotypic transition in recurrent glioblastoma.}},
  author = {Xiaomeng Zhang and Jingru Sui and Haoyuan Sun and Ruichao Chai and Zhaoqi Liu and Jiguang Wang},
  journal = {BMC cancer},
  year = {2026},
  month = jul,
  doi = {10.1186/s12885-026-16597-9},
  url = {https://europepmc.org/article/MED/42919159},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - RBFOX3 is associated with neuronal-like phenotypic transition in recurrent glioblastoma.
AU  - Xiaomeng Zhang
AU  - Jingru Sui
AU  - Haoyuan Sun
AU  - Ruichao Chai
AU  - Zhaoqi Liu
AU  - Jiguang Wang
PY  - 2026
DA  - 2026/07/01
JO  - BMC cancer
DO  - 10.1186/s12885-026-16597-9
UR  - https://europepmc.org/article/MED/42919159
AB  - Background  Emerging 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  We 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  A 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  Dysregulated 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.
SN  - 1471-2407
ER  -