ArticleJournal of experimental & clinical cancer research : CR2026
Mesenchymal stem cell-induced metabolic reprogramming of EGFR-wild-type tumor cells drives therapeutic resistance in EGFR-mutant non-small cell lung cancer.
Article in Journal of experimental & clinical cancer research : CR, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
backgroundTo 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.
methodsIsolate 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.
resultsEGFR-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 patients, 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.
conclusionThese 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.
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