Interpretation of "Single-cell and spatial genomic landscape of non-small cell lung cancer brain metastases"_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

ZOU Shishi , HE Ruyuan , LUO Guoqing , LI Ning ,  GENG Qing

Department of Thoracic Surgery, Wuhan University People's Hospital, Wuhan, 430060, P. R. China;

Corresponding author：

GENG Qing, Email: gengqingwhu@whu.edu.cn

Keywords：

Non-small cell lung cancer; brain metastases; single-cell sequencing; spatial transcriptomics

DOI：

10.7507/1007-4848.202504006

Video：

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Non-small cell lung cancer is one of the primary types of cancer that leads to brain metastases. Approximately 10% of patients with non-small cell lung cancer have brain metastases at the time of diagnosis, and 26%-53% of patients develop brain metastases during the progression of their disease. However, the underlying mechanisms of lung cancer brain metastasis have not been fully elucidated. With the continuous development of single-cell and spatial transcriptomics, the genomic and transcriptomic characteristics of lung cancer brain metastasis are gradually being revealed. In February 2025, the journal Nature Medicine published an article titled "Single-cell and spatial genomic landscape of non-small cell lung cancer brain metastases". This article aims to provide a brief interpretation of the paper for colleagues in research and clinical practice.

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5.	Tagore S, Caprio L, Amin AD, et al. Single-cell and spatial genomic landscape of non-small cell lung cancer brain metastases. Nat Med, 2025, 31(4):1351-1363.
6.	Guo X, Deng Y, Jiang W, et al. Single cell transcriptomic analysis reveals tumor immune infiltration by macrophage cells gene signature in lung adenocarcinoma. Discov Oncol, 2025, 16(1): 261.
7.	Krishnaswami SR, Grindberg RV, Novotny M, et al. Using single nuclei for RNA-seq to capture the transcriptome of postmortem neurons. Nat Protoc, 2016, 11(3): 499-524.
8.	Ding J, Adiconis X, Simmons SK, et al. Systematic comparison of single-cell and single-nucleus RNA-sequencing methods. Nat Biotechnol, 2020, 38(6): 737-746.
9.	Renaut S, Saavedra AV, Boudreau DK, et al. Single-cell and single-nucleus RNA-sequencing from paired normal-adenocarcinoma lung samples provide both common and discordant biological insights. PLoS Genet, 2024, 20(5): e1011301.
10.	Zhao Y, Gao J, Wang J, et al. Genomic and immune heterogeneity of multiple synchronous lung adenocarcinoma at different developmental stages. Nat Commun, 2024, 15(1): 7928.
11.	Ye L, Ryu H, Granadier D, et al. Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma. Transl Lung Cancer Res, 2024, 13(9): 2352-2372.
12.	Gu C, Wang X, Wang K, et al. Cryoablation triggers typeⅠinterferon-dependent antitumor immunity and potentiates immunotherapy efficacy in lung cancer. J Immunother Cancer, 2024, 12(1): e008386.
13.	Rubio-Perez C, Planas-Rigol E, Trincado JL, et al. Immune cell profiling of the cerebrospinal fluid enables the characterization of the brain metastasis microenvironment. Nat Commun, 2021, 12(1): 1503.
14.	Megas S, Wilbrey-Clark A, Maartens A, et al. Spatial transcriptomics of the respiratory system. Annu Rev Physiol, 2025, 87(1): 447-470.
15.	Russell A, Weir JA, Nadaf NM, et al. Slide-tags enables single-nucleus barcoding for multimodal spatial genomics. Nature, 2024, 625(7993): 101-109.
16.	Zhu J, Fan Y, Xiong Y, et al. Delineating the dynamic evolution from preneoplasia to invasive lung adenocarcinoma by integrating single-cell RNA sequencing and spatial transcriptomics. Exp Mol Med, 2022, 54(11): 2060-2076.
17.	Larroquette M, Guegan JP, Besse B, et al. Spatial transcriptomics of macrophage infiltration in non-small cell lung cancer reveals determinants of sensitivity and resistance to anti-PD1/PD-L1 antibodies. J Immunother Cancer, 2022, 10(5): e003890.
18.	Haga Y, Sakamoto Y, Kajiya K, et al. Whole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma. Nat Commun, 2023, 14(1): 8375.
19.	Wang Y, Liu B, Min Q, et al. Spatial transcriptomics delineates molecular features and cellular plasticity in lung adenocarcinoma progression. Cell Discov, 2023, 9(1): 96.
20.	Takano Y, Suzuki J, Nomura K, et al. Spatially resolved gene expression profiling of tumor microenvironment reveals key steps of lung adenocarcinoma development. Nat Commun, 2024, 15(1): 10637.
21.	Jin Y, Wu Y, Reuben A, et al. Single-cell and spatial proteo-transcriptomic profiling reveals immune infiltration heterogeneity associated with neuroendocrine features in small cell lung cancer. Cell Discov, 2024, 10(1): 93.
22.	Peyraud F, Guégan JP, Rey C, et al. Spatially resolved transcriptomics reveal the determinants of primary resistance to immunotherapy in NSCLC with mature tertiary lymphoid structures. Cell Rep Med, 2025, 6(2): 101934.
23.	Li J, Hubisz MJ, Earlie EM, et al. Non-cell-autonomous cancer progression from chromosomal instability. Nature, 2023, 620(7976): 1080-1088.
24.	Zhao M, Wang T, Gleber-Netto FO, et al. Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response. Nat Commun, 2024, 15(1): 180.
25.	Nguyen B, Fong C, Luthra A, et al. Genomic characterization of metastatic patterns from prospective clinical sequencing of 25, 000 patients. Cell, 2022, 185(3): 563-575.
26.	Lengel HB, Mastrogiacomo B, Connolly JG, et al. Genomic mapping of metastatic organotropism in lung adenocarcinoma. Cancer Cell, 2023, 41(5): 970-985.
27.	Zhang C, Wu BZ, Thu KL. Targeting kinesins for therapeutic exploitation of chromosomal instability in lung cancer. Cancers (Basel), 2025, 17(4): 685.
28.	Zeng Q, Michael IP, Zhang P, et al. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature, 2019, 573(7775): 526-531.
29.	Zhang Q, Abdo R, Iosef C, et al. The spatial transcriptomic landscape of non-small cell lung cancer brain metastasis. Nat Commun, 2022, 13(1): 5983.
30.	Wang X, Bai H, Zhang J, et al. Genetic intratumor heterogeneity remodels the immune microenvironment and induces immune evasion in brain metastasis of lung cancer. J Thorac Oncol, 2024, 19(2): 252-272.
31.	Mantovani A, Marchesi F, Di Mitri D, et al. Macrophage diversity in cancer dissemination and metastasis. Cell Mol Immunol, 2024, 21(11): 1201-1214.
32.	Jin Y, Kang Y, Wang M, et al. Targeting polarized phenotype of microglia via IL6/JAK2/STAT3 signaling to reduce NSCLC brain metastasis. Signal Transduct Target Ther, 2022, 7(1): 52.
33.	Duan H, Ren J, Wei S, et al. Integrated analyses of multi-omic data derived from paired primary lung cancer and brain metastasis reveal the metabolic vulnerability as a novel therapeutic target. Genome Med, 2024, 16(1): 138.

1. Cagney DN, Martin AM, Catalano PJ, et al. Incidence and prognosis of patients with brain metastases at diagnosis of systemic malignancy: A population-based study. Neuro Oncol, 2017, 19(11): 1511-1521.
2. Goncalves PH, Peterson SL, Vigneau FD, et al. Risk of brain metastases in patients with nonmetastatic lung cancer: Analysis of the Metropolitan Detroit Surveillance, Epidemiology, and End Results (SEER) data. Cancer, 2016, 122(12): 1921-1927.
3. Zhao W, Zhou W, Rong L, et al. Epidermal growth factor receptor mutations and brain metastases in non-small cell lung cancer. Front Oncol, 2022, 12: 912505.
4. Barlesi F, Tomasini P. Non-small-cell lung cancer brain metastases and PD-(L)1 immune checkpoint inhibitors. Lancet Oncol, 2020, 21(5): 607-608.
5. Tagore S, Caprio L, Amin AD, et al. Single-cell and spatial genomic landscape of non-small cell lung cancer brain metastases. Nat Med, 2025, 31(4):1351-1363.
6. Guo X, Deng Y, Jiang W, et al. Single cell transcriptomic analysis reveals tumor immune infiltration by macrophage cells gene signature in lung adenocarcinoma. Discov Oncol, 2025, 16(1): 261.
7. Krishnaswami SR, Grindberg RV, Novotny M, et al. Using single nuclei for RNA-seq to capture the transcriptome of postmortem neurons. Nat Protoc, 2016, 11(3): 499-524.
8. Ding J, Adiconis X, Simmons SK, et al. Systematic comparison of single-cell and single-nucleus RNA-sequencing methods. Nat Biotechnol, 2020, 38(6): 737-746.
9. Renaut S, Saavedra AV, Boudreau DK, et al. Single-cell and single-nucleus RNA-sequencing from paired normal-adenocarcinoma lung samples provide both common and discordant biological insights. PLoS Genet, 2024, 20(5): e1011301.
10. Zhao Y, Gao J, Wang J, et al. Genomic and immune heterogeneity of multiple synchronous lung adenocarcinoma at different developmental stages. Nat Commun, 2024, 15(1): 7928.
11. Ye L, Ryu H, Granadier D, et al. Stem-like exhausted CD8 T cells in pleural effusions predict improved survival in non-small cell lung cancer (NSCLC) and mesothelioma. Transl Lung Cancer Res, 2024, 13(9): 2352-2372.
12. Gu C, Wang X, Wang K, et al. Cryoablation triggers typeⅠinterferon-dependent antitumor immunity and potentiates immunotherapy efficacy in lung cancer. J Immunother Cancer, 2024, 12(1): e008386.
13. Rubio-Perez C, Planas-Rigol E, Trincado JL, et al. Immune cell profiling of the cerebrospinal fluid enables the characterization of the brain metastasis microenvironment. Nat Commun, 2021, 12(1): 1503.
14. Megas S, Wilbrey-Clark A, Maartens A, et al. Spatial transcriptomics of the respiratory system. Annu Rev Physiol, 2025, 87(1): 447-470.
15. Russell A, Weir JA, Nadaf NM, et al. Slide-tags enables single-nucleus barcoding for multimodal spatial genomics. Nature, 2024, 625(7993): 101-109.
16. Zhu J, Fan Y, Xiong Y, et al. Delineating the dynamic evolution from preneoplasia to invasive lung adenocarcinoma by integrating single-cell RNA sequencing and spatial transcriptomics. Exp Mol Med, 2022, 54(11): 2060-2076.
17. Larroquette M, Guegan JP, Besse B, et al. Spatial transcriptomics of macrophage infiltration in non-small cell lung cancer reveals determinants of sensitivity and resistance to anti-PD1/PD-L1 antibodies. J Immunother Cancer, 2022, 10(5): e003890.
18. Haga Y, Sakamoto Y, Kajiya K, et al. Whole-genome sequencing reveals the molecular implications of the stepwise progression of lung adenocarcinoma. Nat Commun, 2023, 14(1): 8375.
19. Wang Y, Liu B, Min Q, et al. Spatial transcriptomics delineates molecular features and cellular plasticity in lung adenocarcinoma progression. Cell Discov, 2023, 9(1): 96.
20. Takano Y, Suzuki J, Nomura K, et al. Spatially resolved gene expression profiling of tumor microenvironment reveals key steps of lung adenocarcinoma development. Nat Commun, 2024, 15(1): 10637.
21. Jin Y, Wu Y, Reuben A, et al. Single-cell and spatial proteo-transcriptomic profiling reveals immune infiltration heterogeneity associated with neuroendocrine features in small cell lung cancer. Cell Discov, 2024, 10(1): 93.
22. Peyraud F, Guégan JP, Rey C, et al. Spatially resolved transcriptomics reveal the determinants of primary resistance to immunotherapy in NSCLC with mature tertiary lymphoid structures. Cell Rep Med, 2025, 6(2): 101934.
23. Li J, Hubisz MJ, Earlie EM, et al. Non-cell-autonomous cancer progression from chromosomal instability. Nature, 2023, 620(7976): 1080-1088.
24. Zhao M, Wang T, Gleber-Netto FO, et al. Mutant p53 gains oncogenic functions through a chromosomal instability-induced cytosolic DNA response. Nat Commun, 2024, 15(1): 180.
25. Nguyen B, Fong C, Luthra A, et al. Genomic characterization of metastatic patterns from prospective clinical sequencing of 25, 000 patients. Cell, 2022, 185(3): 563-575.
26. Lengel HB, Mastrogiacomo B, Connolly JG, et al. Genomic mapping of metastatic organotropism in lung adenocarcinoma. Cancer Cell, 2023, 41(5): 970-985.
27. Zhang C, Wu BZ, Thu KL. Targeting kinesins for therapeutic exploitation of chromosomal instability in lung cancer. Cancers (Basel), 2025, 17(4): 685.
28. Zeng Q, Michael IP, Zhang P, et al. Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature, 2019, 573(7775): 526-531.
29. Zhang Q, Abdo R, Iosef C, et al. The spatial transcriptomic landscape of non-small cell lung cancer brain metastasis. Nat Commun, 2022, 13(1): 5983.
30. Wang X, Bai H, Zhang J, et al. Genetic intratumor heterogeneity remodels the immune microenvironment and induces immune evasion in brain metastasis of lung cancer. J Thorac Oncol, 2024, 19(2): 252-272.
31. Mantovani A, Marchesi F, Di Mitri D, et al. Macrophage diversity in cancer dissemination and metastasis. Cell Mol Immunol, 2024, 21(11): 1201-1214.
32. Jin Y, Kang Y, Wang M, et al. Targeting polarized phenotype of microglia via IL6/JAK2/STAT3 signaling to reduce NSCLC brain metastasis. Signal Transduct Target Ther, 2022, 7(1): 52.
33. Duan H, Ren J, Wei S, et al. Integrated analyses of multi-omic data derived from paired primary lung cancer and brain metastasis reveal the metabolic vulnerability as a novel therapeutic target. Genome Med, 2024, 16(1): 138.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

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