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Background <p>To explore mesenchymal stem cell (MSC)-driven metabolic reprogramming of EGFR-wild-type (EGFR-wt) tumor cells contributing to tyrosine kinase inhibitor (TKI) resistance in EGFR-mutant (EGFR-mt) non-small cell lung cancer.</p> Methods <p>Isolate MSCs from paired tumor and non-tumor lungs of EGFR-mt and EGFR-wt patients. Integrate transcriptional RNA sequencing, targeted free fatty acid and energy metabolomics to characterize signaling pathways promoting MSC–EGFR-wt tumor cell interaction within EGFR-mt tumors. Assess spatial correlation between these cells in TKI-resistant and TKI-sensitive patients using immunohistochemistry and multiplex immunofluorescence.</p> Results <p>EGFR-mt lung cancer-derived MSCs (mtLC-MSCs) promoted EGFR-wt tumor proliferation, and reduced TKI efficacy in vivo. Mechanistically, mtLC-MSCs increased fatty acid levels, supporting stem-like features in EGFR-wt tumor cells. These effects were mediated by IL-6 and IL-1α secreted from mtLC-MSCs, which enhanced S100A9 expression in EGFR-wt tumor cells and activated downstream c-Myc/β-catenin-FASN signaling, driving fatty acid synthesis. TKI plus IL-6 pathway blockade reversed resistance in mice. In EGFR-mt NSCLC patient, the proportions mtLC-MSCs was comparable with mtTF-MSCs. TKI-resistant samples exhibited greater mtLC-MSCs wrapping density around tumor masses than sensitive samples. EGFR-mt tumor cells showed closer spatial proximity to mtLC-MSCs than did EGFR-wt cells.</p> Conclusion <p>These findings firstly reveal the spatial heterogeneity and metabolic reprograming of EGFR-wt tumor cells driven by mtLC-MSCs in EGFR-mt tumors, providing novel insight into therapeutic resistance and potential combination strategies for TKI-resistant patients.</p>

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Mesenchymal stem cell-induced metabolic reprogramming of EGFR-wild-type tumor cells drives therapeutic resistance in EGFR-mutant non-small cell lung cancer

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Hongyu Bie,
  • Jiarui Li,
  • Jialin Liu,
  • Jian Zhou,
  • Tierun Wang,
  • Xu Guo,
  • Jiawei Liu,
  • Yi You,
  • Hui Huang,
  • Shijia Li,
  • Wanqiao Li,
  • Xiubao Ren,
  • Meng Wang,
  • Wencheng Zhang,
  • Cihui Yan

摘要

Background

To explore mesenchymal stem cell (MSC)-driven metabolic reprogramming of EGFR-wild-type (EGFR-wt) tumor cells contributing to tyrosine kinase inhibitor (TKI) resistance in EGFR-mutant (EGFR-mt) non-small cell lung cancer.

Methods

Isolate MSCs from paired tumor and non-tumor lungs of EGFR-mt and EGFR-wt patients. Integrate transcriptional RNA sequencing, targeted free fatty acid and energy metabolomics to characterize signaling pathways promoting MSC–EGFR-wt tumor cell interaction within EGFR-mt tumors. Assess spatial correlation between these cells in TKI-resistant and TKI-sensitive patients using immunohistochemistry and multiplex immunofluorescence.

Results

EGFR-mt lung cancer-derived MSCs (mtLC-MSCs) promoted EGFR-wt tumor proliferation, and reduced TKI efficacy in vivo. Mechanistically, mtLC-MSCs increased fatty acid levels, supporting stem-like features in EGFR-wt tumor cells. These effects were mediated by IL-6 and IL-1α secreted from mtLC-MSCs, which enhanced S100A9 expression in EGFR-wt tumor cells and activated downstream c-Myc/β-catenin-FASN signaling, driving fatty acid synthesis. TKI plus IL-6 pathway blockade reversed resistance in mice. In EGFR-mt NSCLC patient, the proportions mtLC-MSCs was comparable with mtTF-MSCs. TKI-resistant samples exhibited greater mtLC-MSCs wrapping density around tumor masses than sensitive samples. EGFR-mt tumor cells showed closer spatial proximity to mtLC-MSCs than did EGFR-wt cells.

Conclusion

These findings firstly reveal the spatial heterogeneity and metabolic reprograming of EGFR-wt tumor cells driven by mtLC-MSCs in EGFR-mt tumors, providing novel insight into therapeutic resistance and potential combination strategies for TKI-resistant patients.