Characterization of the pleural microenvironment niche and cancer transition using single-cell RNA sequencing in EGFR-mutated lung cancer

Wu, Yu-Yuan; Hsu, Ya-Ling; Huang, Yung-Chi; Su, Yue-Chiu; Wu, Kuan-Li; Chang, Chao-Yuan; Ong, Chai-Tung; Lai, Jia-Chen; Shen, Tzu-Yen; Lee, Tai-Huang; Hung, Jen-Yu; Tsai, Ying-Ming

doi:10.7150/thno.85084

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Nanotheranostics 2024; 8(4): 442-457. [Abstract] [Full text] [PDF]

Nanotheranostics 2024; 8(4): 427-441. [Abstract] [Full text] [PDF]

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Theranostics 2023; 13(13):4412-4429. doi:10.7150/thno.85084 This issue Cite

Research Paper

Characterization of the pleural microenvironment niche and cancer transition using single-cell RNA sequencing in EGFR-mutated lung cancer

Yu-Yuan Wu^1,2, Ya-Ling Hsu^2,3,*,✉, Yung-Chi Huang², Yue-Chiu Su⁴, Kuan-Li Wu^2,3,5,6, Chao-Yuan Chang⁷, Chai-Tung Ong^2,8, Jia-Chen Lai², Tzu-Yen Shen⁹, Tai-Huang Lee^5,10, Jen-Yu Hung^1,5,10, Ying-Ming Tsai^1,3,5,*,✉

1. School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
2. Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
3. Drug Development and Value Creation Research Center, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
4. Department of Pathology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
5. Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
6. Post Baccalaureate Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
7. Department of Anatomy, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
8. Department of Fragrance and Cosmetic Science, College of Pharmacy, Kaohsiung Medical University, Kaohsiung 807, Taiwan.
9. School of Medicine, College of Medicine, Taipei Medical University, Taipei 110, Taiwan.
10. Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 807, Taiwan.
* Contributed equally.

Citation:

Wu YY, Hsu YL, Huang YC, Su YC, Wu KL, Chang CY, Ong CT, Lai JC, Shen TY, Lee TH, Hung JY, Tsai YM. Characterization of the pleural microenvironment niche and cancer transition using single-cell RNA sequencing in EGFR-mutated lung cancer. Theranostics 2023; 13(13):4412-4429. doi:10.7150/thno.85084. https://www.thno.org/v13p4412.htm

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Abstract

Background: Lung cancer is associated with a high mortality rate and often complicated with malignant pleural effusion (MPE), which has a very poor clinical outcome with a short life expectancy. However, our understanding of cell-specific mechanisms underlying the pathobiology of pleural metastasis remains incomplete.

Methods: We analyzed single-cell transcriptomes of cells in pleural effusion collected from patients with lung cancer and congestive heart failure (as a control), respectively. Soluble and complement factors were measured using a multiplex cytokine bead assay. The role of ferroptosis was evaluated by GPX4 small interfering RNA (siRNA) transfection and overexpression.

Results: We found that the mesothelial-mesenchymal transition (MesoMT) of the pleural mesothelial cells contributed to pleural metastasis, which was validated by lung cancer/mesothelial cell co-culture experiments. The ferroptosis resistance that protected cancer from death which was secondary to extracellular matrix detachment was critical for pleural metastasis. We found a universal presence of immune-suppressive lipid-associated tumor-associated macrophages (LA-TAMs) with complement cascade alteration in the MPE of the lung cancer patients. Specifically, upregulated complement factors were also found in the MPE, and C5 was associated with poor overall survival in the lung cancer patients with epidermal growth factor receptor mutation. Plasmacytoid dendritic cells (pDCs) exhibited a dysfunctional phenotype and pro-tumorigenic feature in the primary cancer. High expression of the gene set extracted from pDCs was associated with a poor prognosis in the lung cancer patients. Receptor-ligand interaction analysis revealed that the pleural metastatic niche was aggravated by cross-talk between mesothelial cells-cancer cells/immune cells via TNC and ICAM1.

Conclusions: Taken together, our results highlight cell-specific mechanisms involved in the pathobiological development of pleural metastasis in lung cancer. These results provide a large-scale and high-dimensional characterization of the pleural microenvironment and offer a useful resource for the future development of therapeutic drugs in lung cancer.

Keywords: Pleural metastasis, complement factor, mesothelial cell, lung cancer, ferroptosis

Citation styles

APA

Wu, Y.Y., Hsu, Y.L., Huang, Y.C., Su, Y.C., Wu, K.L., Chang, C.Y., Ong, C.T., Lai, J.C., Shen, T.Y., Lee, T.H., Hung, J.Y., Tsai, Y.M. (2023). Characterization of the pleural microenvironment niche and cancer transition using single-cell RNA sequencing in EGFR-mutated lung cancer. Theranostics, 13(13), 4412-4429. https://doi.org/10.7150/thno.85084.

ACS

Wu, Y.Y.; Hsu, Y.L.; Huang, Y.C.; Su, Y.C.; Wu, K.L.; Chang, C.Y.; Ong, C.T.; Lai, J.C.; Shen, T.Y.; Lee, T.H.; Hung, J.Y.; Tsai, Y.M. Characterization of the pleural microenvironment niche and cancer transition using single-cell RNA sequencing in EGFR-mutated lung cancer. Theranostics 2023, 13 (13), 4412-4429. DOI: 10.7150/thno.85084.

NLM

CSE

Wu YY, Hsu YL, Huang YC, Su YC, Wu KL, Chang CY, Ong CT, Lai JC, Shen TY, Lee TH, Hung JY, Tsai YM. 2023. Characterization of the pleural microenvironment niche and cancer transition using single-cell RNA sequencing in EGFR-mutated lung cancer. Theranostics. 13(13):4412-4429.

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