Top

Cancer Cell International

Published in:

Open Access 01-12-2024 | Gastric Cancer | Research

Single-cell N⁶-methyladenosine-related genes function within the tumor microenvironment to affect the prognosis and treatment sensitivity in patients with gastric cancer

Authors: Zehua Wang, Chen Chen, Jiao Shu, Jiaoyu Ai, Yihan Liu, Haoyue Cao, Yongxu Jia, Yanru Qin

Published in: Cancer Cell International | Issue 1/2024

Abstract

Background

Gastric cancer (GC) ranks fifth for morbidity and third for mortality worldwide. The N⁶-methyladenosine (m⁶A) mRNA methylation is crucial in cancer biology and progression. However, the relationship between m⁶A methylation and gastric tumor microenvironment (TME) remains to be elucidated.

Methods

We combined single-cell and bulk transcriptome analyses to explore the roles of m⁶A-related genes (MRG) in gastric TME.

Results

Nine TME cell subtypes were identified from 23 samples. Fibroblasts were further grouped into four subclusters according to different cell markers. M⁶A-mediated fibroblasts may guide extensive intracellular communications in the gastric TME. The m⁶A-related genes score (MRGs) was output based on six differentially expressed single-cell m⁶A-related genes (SCMRDEGs), including GHRL, COL4A1, CAV1, GJA1, TIMP1, and IGFBP3. The protein expression level was assessed by immunohistochemistry. We identified the prognostic value of MRGs and constructed a nomogram model to predict GC patients’ overall survival. MRGs may affect treatment sensitivity in GC patients.

Conclusion

Our study visualized the cellular heterogeneity of TME at the single-cell level, revealed the association between m⁶A mRNA modification and intracellular communication, clarified MRGs as an independent risk factor of prognosis, and provided a reference for follow-up treatment.

Available only for authorised users

Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer statistics 2020: GLOBOCAN estimates of incidence and Mortality Worldwide for 36 cancers in 185 countries. Cancer J Clin. 2021;71(3):209–49.CrossRef

Kim ST, Cristescu R, Bass AJ, Kim KM, Odegaard JI, Kim K, et al. Comprehensive molecular characterization of clinical responses to PD-1 inhibition in metastatic gastric cancer. Nat Med. 2018;24(9):1449–58.PubMedCrossRef

Olino K, Park T, Ahuja N. Exposing hidden targets: combining epigenetic and immunotherapy to overcome cancer resistance. Sem Cancer Biol. 2020;65:114–22.CrossRef

Li M, Zha X, Wang S. The role of N6-methyladenosine mRNA in the tumor microenvironment. Biochim et Biophys acta Reviews cancer. 2021;1875(2):188522.CrossRef

Roignant JY, Soller M. M(6)A in mRNA: an ancient mechanism for fine-tuning gene expression. Trends Genet. 2017;33(6):380–90.PubMedCrossRef

Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z, et al. The role of m6A modification in the biological functions and diseases. Signal Transduct Target Therapy. 2021;6(1):74.CrossRef

Wang L, Hui H, Agrawal K, Kang Y, Li N, Tang R, et al. M(6) a RNA methyltransferases METTL3/14 regulate immune responses to anti-PD-1 therapy. EMBO J. 2020;39(20):e104514.PubMedPubMedCentralCrossRef

Yin H, Zhang X, Yang P, Zhang X, Peng Y, Li D, et al. RNA m6A methylation orchestrates cancer growth and metastasis via macrophage reprogramming. Nat Commun. 2021;12(1):1394.PubMedPubMedCentralCrossRef

Papalexi E, Satija R. Single-cell RNA sequencing to explore immune cell heterogeneity. Nat Rev Immunol. 2018;18(1):35–45.PubMedCrossRef

10.

Gonzalez H, Hagerling C, Werb Z. Roles of the immune system in cancer: from tumor initiation to metastatic progression. Genes Dev. 2018;32(19–20):1267–84.PubMedPubMedCentralCrossRef

11.

Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020;20(3):174–86.PubMedPubMedCentralCrossRef

12.

Bruni D, Angell HK, Galon J. The immune contexture and immunoscore in cancer prognosis and therapeutic efficacy. Nat Rev Cancer. 2020;20(11):662–80.PubMedCrossRef

13.

Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, et al. NCBI GEO: archive for functional genomics data sets–update. Nucleic Acids Res. 2013;41(Database issue):D991–5.PubMed

14.

Kim J, Park C, Kim KH, Kim EH, Kim H, Woo JK, et al. Single-cell analysis of gastric pre-cancerous and cancer lesions reveals cell lineage diversity and intratumoral heterogeneity. NPJ Precision Oncology. 2022;6(1):9.PubMedPubMedCentralCrossRef

15.

Mounir M, Lucchetta M, Silva TC, Olsen C, Bontempi G, Chen X, et al. New functionalities in the TCGAbiolinks package for the study and integration of cancer data from GDC and GTEx. PLoS Comput Biol. 2019;15(3):e1006701.PubMedPubMedCentralCrossRef

16.

Zhang X, Lan Y, Xu J, Quan F, Zhao E, Deng C, et al. CellMarker: a manually curated resource of cell markers in human and mouse. Nucleic Acids Res. 2019;47(D1):D721–d8.PubMedCrossRef

17.

Bao X, Zhang Y, Li H, Teng Y, Ma L, Chen Z, et al. RM2Target: a comprehensive database for targets of writers, erasers and readers of RNA modifications. Nucleic Acids Res. 2023;51(D1):D269–d79.PubMedCrossRef

18.

Aibar S, González-Blas CB, Moerman T, Huynh-Thu VA, Imrichova H, Hulselmans G, et al. SCENIC: single-cell regulatory network inference and clustering. Nat Methods. 2017;14(11):1083–6.PubMedPubMedCentralCrossRef

19.

Gene Ontology Consortium. Going forward. Nucleic Acids Res. 2015;43(Database issue):D1049–56.CrossRef

20.

Kanehisa M, Goto S. KEGG: kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 2000;28(1):27–30.PubMedPubMedCentralCrossRef

21.

Qiu X, Mao Q, Tang Y, Wang L, Chawla R, Pliner HA, et al. Reversed graph embedding resolves complex single-cell trajectories. Nat Methods. 2017;14(10):979–82.PubMedPubMedCentralCrossRef

22.

Jin S, Guerrero-Juarez CF, Zhang L, Chang I, Ramos R, Kuan CH, et al. Inference and analysis of cell-cell communication using CellChat. Nat Commun. 2021;12(1):1088.PubMedPubMedCentralCrossRef

23.

Love MI, Huber W, Anders S. Moderated estimation of Fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550.PubMedPubMedCentralCrossRef

24.

Wilkerson MD, Hayes DN. ConsensusClusterPlus: a class discovery tool with confidence assessments and item tracking. Bioinf (Oxford England). 2010;26(12):1572–3.

25.

Heagerty PJ, Lumley T, Pepe MS. Time-dependent ROC curves for censored survival data and a diagnostic marker. Biometrics. 2000;56(2):337–44.PubMedCrossRef

26.

Wang Z, Chen C, Ai J, Shu J, Ding Y, Wang W, et al. Identifying mitophagy-related genes as prognostic biomarkers and therapeutic targets of gastric carcinoma by integrated analysis of single-cell and bulk-RNA sequencing data. Comput Biol Med. 2023;163:107227.PubMedCrossRef

27.

Zeng D, Ye Z, Shen R, Yu G, Wu J, Xiong Y, et al. IOBR: Multi-omics Immuno-Oncology Biological Research to Decode Tumor Microenvironment and signatures. Front Immunol. 2021;12:687975.PubMedPubMedCentralCrossRef

28.

Maeser D, Gruener RF, Huang RS. oncoPredict: an R package for predicting in vivo or cancer patient drug response and biomarkers from cell line screening data. Brief Bioinform. 2021;22(6).

29.

Chen RX, Chen X, Xia LP, Zhang JX, Pan ZZ, Ma XD, et al. N(6)-methyladenosine modification of circNSUN2 facilitates cytoplasmic export and stabilizes HMGA2 to promote colorectal liver metastasis. Nat Commun. 2019;10(1):4695.PubMedPubMedCentralCrossRef

30.

Li T, Hu PS, Zuo Z, Lin JF, Li X, Wu QN, et al. METTL3 facilitates tumor progression via an m(6)A-IGF2BP2-dependent mechanism in colorectal carcinoma. Mol Cancer. 2019;18(1):112.PubMedPubMedCentralCrossRef

31.

Wu Y, Yang X, Chen Z, Tian L, Jiang G, Chen F, et al. M(6)A-induced lncRNA RP11 triggers the dissemination of colorectal cancer cells via upregulation of Zeb1. Mol Cancer. 2019;18(1):87.PubMedPubMedCentralCrossRef

32.

Chen H, Gao S, Liu W, Wong CC, Wu J, Wu J, et al. RNA N(6)-Methyladenosine methyltransferase METTL3 facilitates colorectal Cancer by activating the m(6)A-GLUT1-mTORC1 Axis and is a therapeutic target. Gastroenterology. 2021;160(4):1284–300e16.PubMedCrossRef

33.

Sun L, Wan A, Zhou Z, Chen D, Liang H, Liu C, et al. RNA-binding protein RALY reprogrammes mitochondrial metabolism via mediating miRNA processing in colorectal cancer. Gut. 2021;70(9):1698–712.PubMedCrossRef

34.

Gao Y, Wang H, Chen S, An R, Chu Y, Li G, et al. Single-cell N(6)-methyladenosine regulator patterns guide intercellular communication of tumor microenvironment that contribute to colorectal cancer progression and immunotherapy. J Translational Med. 2022;20(1):197.CrossRef

35.

Xie S, Cai Y, Chen D, Xiang Y, Cai W, Mao J, et al. Single-cell transcriptome analysis reveals heterogeneity and convergence of the tumor microenvironment in colorectal cancer. Front Immunol. 2022;13:1003419.PubMedCrossRef

36.

Galbo PM Jr., Zang X, Zheng D. Molecular features of Cancer-associated fibroblast subtypes and their implication on Cancer Pathogenesis, Prognosis, and Immunotherapy Resistance. Clin cancer Research: Official J Am Association Cancer Res. 2021;27(9):2636–47.CrossRef

37.

Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16(9):582–98.PubMedCrossRef

38.

Miyake M, Hori S, Morizawa Y, Tatsumi Y, Nakai Y, Anai S, et al. CXCL1-Mediated Interaction of Cancer cells with Tumor-Associated macrophages and Cancer-Associated fibroblasts promotes Tumor Progression in human bladder Cancer. New York, NY: Neoplasia; 2016;18(10):636–46.

39.

Kobayashi H, Enomoto A, Woods SL, Burt AD, Takahashi M, Worthley DL. Cancer-associated fibroblasts in gastrointestinal cancer. Nat Reviews Gastroenterol Hepatol. 2019;16(5):282–95.CrossRef

40.

Zhao Q, Huang L, Qin G, Qiao Y, Ren F, Shen C, et al. Cancer-associated fibroblasts induce monocytic myeloid-derived suppressor cell generation via IL-6/exosomal miR-21-activated STAT3 signaling to promote cisplatin resistance in esophageal squamous cell carcinoma. Cancer Lett. 2021;518:35–48.PubMedCrossRef

41.

Dominguez CX, Müller S, Keerthivasan S, Koeppen H, Hung J, Gierke S, et al. Single-cell RNA sequencing reveals stromal evolution into LRRC15(+) myofibroblasts as a determinant of patient response to Cancer Immunotherapy. Cancer Discov. 2020;10(2):232–53.PubMedCrossRef

42.

Kieffer Y, Hocine HR, Gentric G, Pelon F, Bernard C, Bourachot B, et al. Single-cell analysis reveals fibroblast clusters linked to Immunotherapy Resistance in Cancer. Cancer Discov. 2020;10(9):1330–51.PubMedCrossRef

Title: Single-cell N6-methyladenosine-related genes function within the tumor microenvironment to affect the prognosis and treatment sensitivity in patients with gastric cancer
Authors: Zehua Wang
Chen Chen
Jiao Shu
Jiaoyu Ai
Yihan Liu
Haoyue Cao
Yongxu Jia
Yanru Qin
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Gastric Cancer
Gastric Cancer
Published in: Cancer Cell International / Issue 1/2024
Electronic ISSN: 1475-2867
DOI: https://doi.org/10.1186/s12935-024-03227-2

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2024

Platycodin D2 enhances P21/CyclinA2-mediated senescence of HCC cells by regulating NIX-induced mitophagy

MDM2: current research status and prospects of tumor treatment

The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target

Retraction Note: Down-regulation of LINC00472 promotes osteosarcoma tumorigenesis by reducing FOXO1 expressions via miR-300

Alantolactone enhances the sensitivity of melanoma to MAPK pathway inhibitors by targeting inhibition of STAT3 activation and down-regulating stem cell markers

Soluble Periostin is a potential surveillance biomarker for early and long-term response to chemotherapy in advanced breast cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer