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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Vydáno v:	Cell death & disease Ročník 15; číslo 8; s. 580 - 11
Hlavní autoři:	Izumi, Motohiro, Fujii, Masanori, Kobayashi, Ikei S., Ho, Vivian, Kashima, Yukie, Udagawa, Hibiki, Costa, Daniel B., Kobayashi, Susumu S.
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 09.08.2024 Springer Nature B.V Nature Publishing Group
Témata:	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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Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	2041-4889 2041-4889
DOI:	10.1038/s41419-024-06940-y