Single-cell RNA Sequencing Demonstrates the Molecular and Cellular Reprogramming of Metastatic Lung Adenocarcinoma

Overview

Journal Nat Commun

Specialty Biology

Date 2020 May 10

PMID 32385277

Citations 507

Authors

Nayoung Kim

Hong Kwan Kim

Kyungjong Lee

Yourae Hong

Jong Ho Cho

Jung Won Choi

Jung-Il Lee

Yeon-Lim Suh

Bo Mi Ku

Hye Hyeon Eum

Soyean Choi

Yoon-La Choi

Je-Gun Joung

Woong-Yang Park

Hyun Ae Jung

Jong-Mu Sun

Se-Hoon Lee

Jin Seok Ahn

Keunchil Park

Myung-Ju Ahn

Hae-Ock Lee

Affiliations

Soon will be listed here.

Abstract

Advanced metastatic cancer poses utmost clinical challenges and may present molecular and cellular features distinct from an early-stage cancer. Herein, we present single-cell transcriptome profiling of metastatic lung adenocarcinoma, the most prevalent histological lung cancer type diagnosed at stage IV in over 40% of all cases. From 208,506 cells populating the normal tissues or early to metastatic stage cancer in 44 patients, we identify a cancer cell subtype deviating from the normal differentiation trajectory and dominating the metastatic stage. In all stages, the stromal and immune cell dynamics reveal ontological and functional changes that create a pro-tumoral and immunosuppressive microenvironment. Normal resident myeloid cell populations are gradually replaced with monocyte-derived macrophages and dendritic cells, along with T-cell exhaustion. This extensive single-cell analysis enhances our understanding of molecular and cellular dynamics in metastatic lung cancer and reveals potential diagnostic and therapeutic targets in cancer-microenvironment interactions.

Citing Articles

Analyze the Diversity and Function of Immune Cells in the Tumor Microenvironment From the Perspective of Single-Cell RNA Sequencing.

Ma L, Luan Y, Lu L Cancer Med. 2025; 14(5):e70622.

PMID: 40062730 PMC: 11891933. DOI: 10.1002/cam4.70622.

Tissue macrophages: origin, heterogenity, biological functions, diseases and therapeutic targets.

Guan F, Wang R, Yi Z, Luo P, Liu W, Xie Y Signal Transduct Target Ther. 2025; 10(1):93.

PMID: 40055311 PMC: 11889221. DOI: 10.1038/s41392-025-02124-y.

Single cell transcriptomic analysis reveals tumor immune infiltration by macrophage cells gene signature in lung adenocarcinoma.

Guo X, Deng Y, Jiang W, Li H, Luo Y, Zhang H Discov Oncol. 2025; 16(1):261.

PMID: 40029500 PMC: 11876514. DOI: 10.1007/s12672-025-01834-7.

Identification of blood-derived exosomal tumor RNA signatures as noninvasive diagnostic biomarkers for multi-cancer: a multi-phase, multi-center study.

Wang F, Wang C, Chen S, Wei C, Ji J, Liu Y Mol Cancer. 2025; 24(1):60.

PMID: 40025576 PMC: 11871737. DOI: 10.1186/s12943-025-02271-4.

Dissecting tumor cell programs through group biology estimation in clinical single-cell transcriptomics.

Johri S, Bi K, Titchen B, Fu J, Conway J, Crowdis J Nat Commun. 2025; 16(1):2090.

PMID: 40025015 PMC: 11873288. DOI: 10.1038/s41467-025-57377-6.

References

Riihimaki M, Hemminki A, Fallah M, Thomsen H, Sundquist K, Sundquist J . Metastatic sites and survival in lung cancer. Lung Cancer. 2014; 86(1):78-84. DOI: 10.1016/j.lungcan.2014.07.020. View

Larsen J, Minna J . Molecular biology of lung cancer: clinical implications. Clin Chest Med. 2011; 32(4):703-40. PMC: 3367865. DOI: 10.1016/j.ccm.2011.08.003. View

Popper H . Progression and metastasis of lung cancer. Cancer Metastasis Rev. 2016; 35(1):75-91. PMC: 4821869. DOI: 10.1007/s10555-016-9618-0. View

Chae Y, Arya A, Iams W, Cruz M, Chandra S, Choi J . Current landscape and future of dual anti-CTLA4 and PD-1/PD-L1 blockade immunotherapy in cancer; lessons learned from clinical trials with melanoma and non-small cell lung cancer (NSCLC). J Immunother Cancer. 2018; 6(1):39. PMC: 5956851. DOI: 10.1186/s40425-018-0349-3. View

Binnewies M, Roberts E, Kersten K, Chan V, Fearon D, Merad M . Understanding the tumor immune microenvironment (TIME) for effective therapy. Nat Med. 2018; 24(5):541-550. PMC: 5998822. DOI: 10.1038/s41591-018-0014-x. View

Azizi E, Carr A, Plitas G, Cornish A, Konopacki C, Prabhakaran S . Single-Cell Map of Diverse Immune Phenotypes in the Breast Tumor Microenvironment. Cell. 2018; 174(5):1293-1308.e36. PMC: 6348010. DOI: 10.1016/j.cell.2018.05.060. View

Lambrechts D, Wauters E, Boeckx B, Aibar S, Nittner D, Burton O . Phenotype molding of stromal cells in the lung tumor microenvironment. Nat Med. 2018; 24(8):1277-1289. DOI: 10.1038/s41591-018-0096-5. View

Guo X, Zhang Y, Zheng L, Zheng C, Song J, Zhang Q . Global characterization of T cells in non-small-cell lung cancer by single-cell sequencing. Nat Med. 2018; 24(7):978-985. DOI: 10.1038/s41591-018-0045-3. View

Lavin Y, Kobayashi S, Leader A, Amir E, Elefant N, Bigenwald C . Innate Immune Landscape in Early Lung Adenocarcinoma by Paired Single-Cell Analyses. Cell. 2017; 169(4):750-765.e17. PMC: 5737939. DOI: 10.1016/j.cell.2017.04.014. View

10.

Rowbotham S, Kim C . Diverse cells at the origin of lung adenocarcinoma. Proc Natl Acad Sci U S A. 2014; 111(13):4745-6. PMC: 3977312. DOI: 10.1073/pnas.1401955111. View

11.

Patel A, Tirosh I, Trombetta J, Shalek A, Gillespie S, Wakimoto H . Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014; 344(6190):1396-401. PMC: 4123637. DOI: 10.1126/science.1254257. View

12.

Qiu X, Mao Q, Tang Y, Wang L, Chawla R, Pliner H . Reversed graph embedding resolves complex single-cell trajectories. Nat Methods. 2017; 14(10):979-982. PMC: 5764547. DOI: 10.1038/nmeth.4402. View

13.

Cheung W, Nguyen D . Lineage factors and differentiation states in lung cancer progression. Oncogene. 2015; 34(47):5771-80. PMC: 7597437. DOI: 10.1038/onc.2015.85. View

14.

Blanco R, Gerhardt H . VEGF and Notch in tip and stalk cell selection. Cold Spring Harb Perspect Med. 2012; 3(1):a006569. PMC: 3530037. DOI: 10.1101/cshperspect.a006569. View

15.

Zhao Q, Eichten A, Parveen A, Adler C, Huang Y, Wang W . Single-Cell Transcriptome Analyses Reveal Endothelial Cell Heterogeneity in Tumors and Changes following Antiangiogenic Treatment. Cancer Res. 2018; 78(9):2370-2382. DOI: 10.1158/0008-5472.CAN-17-2728. View

16.

Hellstrom M, Phng L, Gerhardt H . VEGF and Notch signaling: the yin and yang of angiogenic sprouting. Cell Adh Migr. 2009; 1(3):133-6. PMC: 2634014. DOI: 10.4161/cam.1.3.4978. View

17.

Thomas J, Baker K, Han J, Calvo C, Nurmi H, Eichmann A . Interactions between VEGFR and Notch signaling pathways in endothelial and neural cells. Cell Mol Life Sci. 2013; 70(10):1779-92. PMC: 3648205. DOI: 10.1007/s00018-013-1312-6. View

18.

Nowak-Sliwinska P, van Beijnum J, Huijbers E, Gasull P, Mans L, Bex A . Oncofoetal insulin receptor isoform A marks the tumour endothelium; an underestimated pathway during tumour angiogenesis and angiostatic treatment. Br J Cancer. 2018; 120(2):218-228. PMC: 6342959. DOI: 10.1038/s41416-018-0347-8. View

19.

Hall R, Le T, Haggstrom D, Gentzler R . Angiogenesis inhibition as a therapeutic strategy in non-small cell lung cancer (NSCLC). Transl Lung Cancer Res. 2015; 4(5):515-23. PMC: 4630516. DOI: 10.3978/j.issn.2218-6751.2015.06.09. View

20.

Kim W, Lee H . Brain angiogenesis in developmental and pathological processes: mechanism and therapeutic intervention in brain tumors. FEBS J. 2009; 276(17):4653-64. PMC: 2847309. DOI: 10.1111/j.1742-4658.2009.07177.x. View