Integration of bulk and single-cell transcriptomics via the Scissor algorithm reveals APOE-dependent cholesterol metabolic reprogramming in macrophages associated with osimertinib resistance in non-small cell lung cancer
Abstract
BackgroundThe tumor microenvironment contributes to acquired resistance against osimertinib in non-small cell lung cancer (NSCLC), yet the key cell subpopulations and the underlying metabolic mechanisms remain incompletely elucidated.MethodsThe Scissor algorithm was applied to integrate bulk osimertinib-resistance transcriptomic profiles with single-cell RNA-seq data to pinpoint cell subpopulations functionally associated with the osimertinib resistant phenotype. AddModuleScore was applied to calculate scores for cholesterol metabolism-related modules. Gene-set enrichment analysis was carried out to uncover pathway alterations in osimertinib resistance-related macrophages. Cross-validation was performed in an independent dataset comparing treatment-naive and EGFR-tyrosine kinase inhibitors (EGFR-TKIs)-treated progressive-disease lesions. EGFR-mutant lung adenocarcinoma cells were treated with corresponding conditioned medium combined with osimertinib, followed by a panel of cell function assays, including cell proliferation, colony formation, and apoptosis. The gain- and loss- of function studies of APOE were conducted in THP-1 derived macrophages.ResultsOsimertinib-resistant associated Scissor+ cells were mainly enriched within macrophages, which exhibited prominent APOE-dependent cholesterol metabolic reprogramming. APOE was markedly up-regulated in Scissor+ macrophages and macrophages from EGFR-TKI-treated progressive-disease lesions. Macrophage-derived APOE shapes extracellular cholesterol availability in the microenvironment, which may promote intracellular free-cholesterol accumulation in tumor cells and counteract osimertinib-triggered apoptosis.ConclusionAPOE-dependent cholesterol metabolic reprogramming in macrophages is associated with osimertinib resistance in NSCLC and may contribute to therapeutic failure. Our results identify APOE as a hypothesis-generating candidate molecule that merits further pre-clinical investigation.
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BibTeX
@article{gong2026integration,
title = {{Integration of bulk and single-cell transcriptomics via the Scissor algorithm reveals APOE-dependent cholesterol metabolic reprogramming in macrophages associated with osimertinib resistance in non-small cell lung cancer}},
author = {Zhiyuan Gong and Zhao Gao and Jiachang Zhang and Limin Cao and Qicheng Zhang and Luoyi Li and Yidan Jia and Ke Xu},
journal = {Frontiers in Immunology},
year = {2026},
month = nov,
doi = {10.3389/fimmu.2026.2001435},
url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.2001435},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Integration of bulk and single-cell transcriptomics via the Scissor algorithm reveals APOE-dependent cholesterol metabolic reprogramming in macrophages associated with osimertinib resistance in non-small cell lung cancer
AU - Zhiyuan Gong
AU - Zhao Gao
AU - Jiachang Zhang
AU - Limin Cao
AU - Qicheng Zhang
AU - Luoyi Li
AU - Yidan Jia
AU - Ke Xu
PY - 2026
DA - 2026/11/09
JO - Frontiers in Immunology
DO - 10.3389/fimmu.2026.2001435
UR - https://www.frontiersin.org/articles/10.3389/fimmu.2026.2001435
AB - BackgroundThe tumor microenvironment contributes to acquired resistance against osimertinib in non-small cell lung cancer (NSCLC), yet the key cell subpopulations and the underlying metabolic mechanisms remain incompletely elucidated.MethodsThe Scissor algorithm was applied to integrate bulk osimertinib-resistance transcriptomic profiles with single-cell RNA-seq data to pinpoint cell subpopulations functionally associated with the osimertinib resistant phenotype. AddModuleScore was applied to calculate scores for cholesterol metabolism-related modules. Gene-set enrichment analysis was carried out to uncover pathway alterations in osimertinib resistance-related macrophages. Cross-validation was performed in an independent dataset comparing treatment-naive and EGFR-tyrosine kinase inhibitors (EGFR-TKIs)-treated progressive-disease lesions. EGFR-mutant lung adenocarcinoma cells were treated with corresponding conditioned medium combined with osimertinib, followed by a panel of cell function assays, including cell proliferation, colony formation, and apoptosis. The gain- and loss- of function studies of APOE were conducted in THP-1 derived macrophages.ResultsOsimertinib-resistant associated Scissor+ cells were mainly enriched within macrophages, which exhibited prominent APOE-dependent cholesterol metabolic reprogramming. APOE was markedly up-regulated in Scissor+ macrophages and macrophages from EGFR-TKI-treated progressive-disease lesions. Macrophage-derived APOE shapes extracellular cholesterol availability in the microenvironment, which may promote intracellular free-cholesterol accumulation in tumor cells and counteract osimertinib-triggered apoptosis.ConclusionAPOE-dependent cholesterol metabolic reprogramming in macrophages is associated with osimertinib resistance in NSCLC and may contribute to therapeutic failure. Our results identify APOE as a hypothesis-generating candidate molecule that merits further pre-clinical investigation.
SN - 1664-3224
ER -