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<p>Glioblastoma is a highly aggressive brain tumor characterized by substantial intratumoral heterogeneity and poor clinical outcomes. Understanding the transcriptional programs and microenvironmental cues that drive aggressive tumor cell states is essential for developing targeted therapies.&#xa0;We integrated bulk and single-cell RNA-seq data from TCGA, CGGA, and published spatial datasets. Using BayesPrism deconvolution, we identified a glioblastoma subpopulation (G1) whose abundance consistently correlated with poor prognosis. Pseudotime analysis with Monocle2 positioned G1 at the terminal state of malignant differentiation. To uncover regulatory mechanisms, we applied NetAct and SCENIC, which highlighted KLF10 as a key transcription factor. Spatial transcriptomic deconvolution and NicheNet analysis suggest that microenvironment-derived TNF likely drives G1 transition via FAT1/TNFRSF1A and ceruloplasmin (CP) induction. Functional experiments including CCK-8, EdU, Transwell, and wound healing assays validated the TNF/CP/KLF10 axis as a driver of glioblastoma cell proliferation and migration.&#xa0;Among the eight glioma cell subtypes identified, the G1 subtype was consistently associated with poor prognosis and showed higher proliferation and migration scores. G1 cells showed enhanced ER stress signaling. Integrated analysis identified TNF-α as a key ligand secreted by cDCs, macrophages, and microglia within G1-enriched spatial niches. FAT1 and TNFRSF1A were identified as G1-specific TNF receptors. Transcription factor KLF10 was identified as a master regulator of G1 identity. Functional assays demonstrated that TNF-α promotes glioblastoma cell proliferation and migration through a CP/KLF10 axis, wherein TNF-α-induced CP upregulation modulates KLF10 expression, and these biological effects were reversed by CP suppression.&#xa0;Our study defines a malignant glioblastoma cell state (G1) regulated by intrinsic transcriptional programs and extrinsic immune-derived TNF–CP signaling. Targeting the G1 program or interrupting the TNF-α/CP/KLF10 axis may offer new therapeutic strategies for glioblastoma. </p>

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Single-cell and spatial transcriptomics reveal TNF-α promotes glioblastoma proliferation and migration via CP-mediated KLF10 upregulation

  • 期刊论文

  • 发表日期：

    2026年4月11日

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  • Jiasheng Zhong,
  • Zechuan Peng,
  • Hongyi Cai,
  • Yunhe Zhao,
  • Liya Ma,
  • Yiquan Ke,
  • Xinlin Sun

摘要

Glioblastoma is a highly aggressive brain tumor characterized by substantial intratumoral heterogeneity and poor clinical outcomes. Understanding the transcriptional programs and microenvironmental cues that drive aggressive tumor cell states is essential for developing targeted therapies. We integrated bulk and single-cell RNA-seq data from TCGA, CGGA, and published spatial datasets. Using BayesPrism deconvolution, we identified a glioblastoma subpopulation (G1) whose abundance consistently correlated with poor prognosis. Pseudotime analysis with Monocle2 positioned G1 at the terminal state of malignant differentiation. To uncover regulatory mechanisms, we applied NetAct and SCENIC, which highlighted KLF10 as a key transcription factor. Spatial transcriptomic deconvolution and NicheNet analysis suggest that microenvironment-derived TNF likely drives G1 transition via FAT1/TNFRSF1A and ceruloplasmin (CP) induction. Functional experiments including CCK-8, EdU, Transwell, and wound healing assays validated the TNF/CP/KLF10 axis as a driver of glioblastoma cell proliferation and migration. Among the eight glioma cell subtypes identified, the G1 subtype was consistently associated with poor prognosis and showed higher proliferation and migration scores. G1 cells showed enhanced ER stress signaling. Integrated analysis identified TNF-α as a key ligand secreted by cDCs, macrophages, and microglia within G1-enriched spatial niches. FAT1 and TNFRSF1A were identified as G1-specific TNF receptors. Transcription factor KLF10 was identified as a master regulator of G1 identity. Functional assays demonstrated that TNF-α promotes glioblastoma cell proliferation and migration through a CP/KLF10 axis, wherein TNF-α-induced CP upregulation modulates KLF10 expression, and these biological effects were reversed by CP suppression. Our study defines a malignant glioblastoma cell state (G1) regulated by intrinsic transcriptional programs and extrinsic immune-derived TNF–CP signaling. Targeting the G1 program or interrupting the TNF-α/CP/KLF10 axis may offer new therapeutic strategies for glioblastoma.