Integrative single-cell RNA-seq and spatial transcriptomics analyses reveal diverse apoptosis-related gene expression profiles in EGFR-mutated lung cancer

In EGFR -mutated lung cancer, the duration of response to tyrosine kinase inhibitors (TKIs) is limited by the development of acquired drug resistance. Despite the crucial role played by apoptosis-related genes in tumor cell survival, how their expression changes as resistance to EGFR-TKIs emerges re...

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Veröffentlicht in:Cell death & disease Jg. 15; H. 8; S. 580 - 11
Hauptverfasser: Izumi, Motohiro, Fujii, Masanori, Kobayashi, Ikei S., Ho, Vivian, Kashima, Yukie, Udagawa, Hibiki, Costa, Daniel B., Kobayashi, Susumu S.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: London Nature Publishing Group UK 09.08.2024
Springer Nature B.V
Nature Publishing Group
Schlagworte:
13/1
13/109
38/39
38/91
631/337/2019
631/67/1612/1350
Animals
Antibodies
Apoptosis
Apoptosis - drug effects
Apoptosis - genetics
Bcl-2 protein
Bcl-x protein
bcl-X Protein - genetics
bcl-X Protein - metabolism
Biochemistry
Biomedical and Life Sciences
Cell Biology
Cell Culture
Cell Line, Tumor
Cell survival
Drug resistance
Drug Resistance, Neoplasm - genetics
Epidermal growth factor receptors
ErbB Receptors - genetics
ErbB Receptors - metabolism
Gene expression
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genetic analysis
Humans
Immunology
Kinases
Life Sciences
Lung cancer
Lung Neoplasms - drug therapy
Lung Neoplasms - genetics
Lung Neoplasms - metabolism
Lung Neoplasms - pathology
Mcl-1 protein
Mice
Mice, Transgenic
Mutation - genetics
Nucleotide sequence
Protein Kinase Inhibitors - pharmacology
RNA-Seq
Single-Cell Analysis
Single-Cell Gene Expression Analysis
Spatial heterogeneity
Transcriptome - genetics
Transcriptomics
Transgenic mice
Tumor cell lines
Tumor cells
Tumors
Tyrosine kinase inhibitors
ISSN:2041-4889, 2041-4889
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Zusammenfassung:In EGFR -mutated lung cancer, the duration of response to tyrosine kinase inhibitors (TKIs) is limited by the development of acquired drug resistance. Despite the crucial role played by apoptosis-related genes in tumor cell survival, how their expression changes as resistance to EGFR-TKIs emerges remains unclear. Here, we conduct a comprehensive analysis of apoptosis-related genes, including BCL-2 and IAP family members, using single-cell RNA sequence ( scRNA-seq) and spatial transcriptomics (ST). scRNA-seq of EGFR -mutated lung cancer cell lines captures changes in apoptosis-related gene expression following EGFR-TKI treatment, most notably BCL2L1 upregulation. scRNA-seq of EGFR -mutated lung cancer patient samples also reveals high BCL2L1 expression, specifically in tumor cells, while MCL1 expression is lower in tumors compared to non-tumor cells. ST analysis of specimens from transgenic mice with EGFR-driven lung cancer indicates spatial heterogeneity of tumors and corroborates scRNA-seq findings. Genetic ablation and pharmacological inhibition of BCL2L1 /BCL-XL overcome or delay EGFR-TKI resistance. Overall, our findings indicate that BCL2L1 /BCL-XL expression is important for tumor cell survival as EGFR-TKI resistance emerges.
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ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-024-06940-y