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Single-cell and spatial transcriptomics reveal a potential role of ATF3 in brain metastasis of lung adenocarcinoma
Chaoliang Xu1, Jingpiao Bao2,3, Deshen Pan1
1Department of Thoracic Surgery, Institute of Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Background:
Brain metastasis (BrM) has been a challenge for lung cancer treatment, but the mechanisms underlying lung cancer BrM remain elusive. This study aims to dissect cellular components and their spatial distribution in human BrM tumors of lung adenocarcinoma (LUAD) and identify potential therapeutic targets.
Methods:
We performed single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) on three LUAD BrMs, and validated our findings using public scRNA-seq data of 10 LUAD BrMs. Western blotting, quantitative real-time polymerase chain reaction (qRT-PCR) and functional experiments were employed for experimental studies.
Results:
By combining scRNA-seq and ST, our analysis revealed the inter- and intra-tumoral heterogeneity of cellular components and their spatial localization within LUAD BrMs. Through RNA velocity and transcription factor (TF) regulatory activity analyses, we identified ATF3 as a potential regulator of the mesenchymal-epithelial transition (MET) program, which plays crucial roles in the colonization of tumor cells at metastatic sites. Furthermore, we demonstrated that knockdown of ATF3 significantly inhibited cancer cell proliferation while promoting cancer cell migration. Mechanistically, ATF3 knockdown could reverse the MET program. Additionally, we revealed that LGALS3/ANXA2-mediated cell-cell interaction between macrophage and tumor cells may also promote the MET program.
Conclusions:
Our study provides a single-cell atlas of the cellular composition in BrM of LUAD and identifies ATF3 as a potential therapeutic target for BrM treatment.
Insights
This study reveals key cellular players and their locations in lung adenocarcinoma brain metastases. It identifies ATF3 as a promising therapeutic target to inhibit cancer cell growth and spread.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Brain metastasis (BrM) presents a significant challenge in lung cancer treatment.
- The underlying mechanisms of lung cancer BrM are not fully understood.
- This study focuses on lung adenocarcinoma (LUAD) BrM.
Purpose of the Study:
- To dissect cellular components and their spatial distribution in human LUAD BrM tumors.
- To identify potential therapeutic targets for LUAD BrM.
Main Methods:
- Single-cell RNA sequencing (scRNA-seq) and spatial transcriptomics (ST) were performed on LUAD BrM samples.
- Findings were validated using public scRNA-seq data and experimental methods like Western blotting and qRT-PCR.
- RNA velocity and transcription factor (TF) regulatory activity analyses were employed.
Main Results:
- Analysis revealed inter- and intra-tumoral heterogeneity and spatial localization of cellular components in LUAD BrMs.
- ATF3 was identified as a potential regulator of the mesenchymal-epithelial transition (MET) program.
- Knockdown of ATF3 inhibited cancer cell proliferation, promoted migration, and reversed the MET program. Macrophage-tumor cell interactions via LGALS3/ANXA2 also promote MET.
Conclusions:
- The study provides a single-cell atlas of cellular composition in LUAD BrM.
- ATF3 is identified as a potential therapeutic target for treating brain metastasis in lung cancer.
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