Skip to main content

Advertisement

SpringerLink
Log in

Single-cell sequencing and bulk RNA data reveal the tumor microenvironment infiltration characteristics of disulfidptosis related genes in breast cancer

  • Research
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Immunotherapy, represented by immune checkpoint inhibitors, has made significant progress in the treatment of cancer. Numerous studies have demonstrated that antitumor therapies targeting cell death exhibit synergistic effects with immunotherapy. Disulfidptosis is a recently discovered form of cell death, and its potential influence on immunotherapy, similar to other regulated cell death processes, requires further investigation. The prognostic value of disulfidptosis in breast cancer and its role in the immune microenvironment has not been investigated.

Methods

High dimensional weighted gene coexpression network analysis (hdWGCNA) and Weighted co-expression network analysis (WGCNA) methods were employed to integrate breast cancer single-cell sequencing data and bulk RNA data. These analyses aimed to identify genes associated with disulfidptosis in breast cancer. Risk assessment signature was constructed using Univariate Cox and least absolute shrinkage and selection operator (LASSO) analyses.

Results

In this study, we constructed a risk signature by disulfidptosis-related genes to predict overall survival and immunotherapy response in BRCA patients. The risk signature demonstrated robust prognostic power and accurately predicted survival compared to traditional clinicopathological features. It also effectively predicted the response to immunotherapy in patients with breast cancer. Through cell communication analysis in additional single-cell sequencing data, we identified TNFRSF14 as a key regulatory gene. Combining TNFRSF14 targeting and immune checkpoint inhibition to induce disulfidptosis in tumor cells could potentially suppress tumor proliferation and enhance survival in patients with BRCA.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data availability

The original contributions presented in the study are included in the article/Supplementary Material. Further inquiries can be directed to the corresponding authors.

References

  • Adams S, Gatti-Mays ME, Kalinsky K, Korde LA, Sharon E, Amiri-Kordestani L et al (2019) Current landscape of immunotherapy in breast cancer: a review. JAMA Oncol 5(8):1205–1214

    PubMed  PubMed Central  Google Scholar 

  • Cao D, Xu H, Xu X, Guo T, Ge W (2019) High tumor mutation burden predicts better efficacy of immunotherapy: a pooled analysis of 103078 cancer patients. OncoImmunology 8(9):e1629258

    PubMed  PubMed Central  Google Scholar 

  • CD36-mediated ferroptosis dampens intratumoral CD8+ T cell effector function and impairs their antitumor ability - PubMed [Internet]. [cited 2023 May 28]. Available from: https://pubmed.ncbi.nlm.nih.gov/33691090/

  • Cella D, Motzer RJ, Suarez C, Blum SI, Ejzykowicz F, Hamilton M et al (2022) Patient-reported outcomes with first-line nivolumab plus cabozantinib versus sunitinib in patients with advanced renal cell carcinoma treated in CheckMate 9ER: an open-label, randomised, phase 3 trial. Lancet Oncol 23(2):292–303

    CAS  PubMed  PubMed Central  Google Scholar 

  • De novo induction of intratumoral lymphoid structures and vessel normalization enhances immunotherapy in resistant tumors | Nature Immunology [Internet]. [cited 2023 May 28]. Available from: https://www.nature.com/articles/ni.3836

  • Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S et al (2022) Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med 386(5):449–462

    CAS  PubMed  Google Scholar 

  • Drijvers JM, Gillis JE, Muijlwijk T, Nguyen TH, Gaudiano EF, Harris IS et al (2021) Pharmacologic screening identifies metabolic vulnerabilities of CD8+ T cells. Cancer Immunol Res 9(2):184–199

    CAS  PubMed  Google Scholar 

  • Du Y, Liu Z, You L, Hou P, Ren X, Jiao T et al (2017) Pancreatic cancer progression relies upon mutant p53-induced oncogenic signaling mediated by NOP14. Cancer Res 77(10):2661–2673

    CAS  PubMed  Google Scholar 

  • Feng X, Luo Q, Zhang H, Wang H, Chen W, Meng G et al (2017) The role of NLRP3 inflammasome in 5-fluorouracil resistance of oral squamous cell carcinoma. J Exp Clin Cancer Res CR 36(1):81

    PubMed  Google Scholar 

  • Frontiers | Integrating single-cell RNA-seq and bulk RNA-seq to construct prognostic signatures to explore the role of glutamine metabolism in breast cancer [Internet]. [cited 2023 May 27]. Available from: https://www.frontiersin.org/articles/https://doi.org/10.3389/fendo.2023.1135297/full

  • Fu W, Sun H, Zhao Y, Chen M, Yang X, Liu Y et al (2019) BCAP31 drives TNBC development by modulating ligand-independent EGFR trafficking and spontaneous EGFR phosphorylation. Theranostics 9(22):6468–6484

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fuchs Y, Steller H (2015) Live to die another way: modes of programmed cell death and the signals emanating from dying cells. Nat Rev Mol Cell Biol 16(6):329–344

    CAS  PubMed  Google Scholar 

  • Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P et al (2018) Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ 25(3):486–541

    PubMed  PubMed Central  Google Scholar 

  • Gao W, Wang X, Zhou Y, Wang X, Yu Y (2022) Autophagy, ferroptosis, pyroptosis, and necroptosis in tumor immunotherapy. Signal Transduct Target Ther 7(1):196

    PubMed  PubMed Central  Google Scholar 

  • García-Hernández M de la L, Uribe-Uribe NO, Espinosa-González R, Kast WM, Khader SA, Rangel-Moreno J. A unique cellular and molecular microenvironment is present in tertiary lymphoid organs of patients with spontaneous prostate cancer regression. Front Immunol [Internet]. 2017 [cited 2023 May 28];8. Available from: https://www.frontiersin.org/articles/https://doi.org/10.3389/fimmu.2017.00563

  • Hänzelmann S, Castelo R, Guinney J (2013) GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinformatics 14:7

    PubMed  PubMed Central  Google Scholar 

  • Harari A, Graciotti M, Bassani-Sternberg M, Kandalaft LE (2020) Antitumour dendritic cell vaccination in a priming and boosting approach. Nat Rev Drug Discov 19(9):635–652

    CAS  PubMed  Google Scholar 

  • He B, Jabouille A, Steri V, Johansson-Percival A, Michael IP, Kotamraju VR et al (2018) Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules. J Pathol 245(2):209–221

    CAS  PubMed  PubMed Central  Google Scholar 

  • Hernandez R, Põder J, LaPorte KM, Malek TR (2022) Engineering IL-2 for immunotherapy of autoimmunity and cancer. Nat Rev Immunol 22(10):614–628

    CAS  PubMed  Google Scholar 

  • Hua X, Long ZQ, Zhang YL, Wen W, Guo L, Xia W, et al. Prognostic value of preoperative systemic immune-inflammation index in breast cancer: a propensity score-matching study. Front Oncol [Internet]. 2020 [cited 2023 May 27];10. Available from: https://www.frontiersin.org/articles/https://doi.org/10.3389/fonc.2020.00580

  • Hugo W, Zaretsky JM, Sun L, Song C, Moreno BH, Hu-Lieskovan S et al (2016) Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165(1):35–44

    CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang X, Stockwell BR, Conrad M (2021) Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol 22(4):266–282

    PubMed  PubMed Central  Google Scholar 

  • Johansson-Percival A, Li ZJ, Lakhiani DD, He B, Wang X, Hamzah J et al (2015) Intratumoral LIGHT restores pericyte contractile properties and vessel integrity. Cell Rep 13(12):2687–2698

    CAS  PubMed  Google Scholar 

  • Kapralov AA, Yang Q, Dar HH, Tyurina YY, Anthonymuthu TS, Kim R et al (2020) Redox lipid reprogramming commands susceptibility of macrophages and microglia to ferroptotic death. Nat Chem Biol 16(3):278–290

    CAS  PubMed  PubMed Central  Google Scholar 

  • Keenan TE, Tolaney SM (2020) Role of immunotherapy in triple-negative breast cancer. J Natl Compr Cancer Netw JNCCN 18(4):479–489

    CAS  PubMed  Google Scholar 

  • Korman AJ, Garrett-Thomson SC, Lonberg N (2022) The foundations of immune checkpoint blockade and the ipilimumab approval decennial. Nat Rev Drug Discov 21(7):509–528

    CAS  PubMed  Google Scholar 

  • Lang X, Green MD, Wang W, Yu J, Choi JE, Jiang L et al (2019) Radiotherapy and immunotherapy promote tumoral lipid oxidation and ferroptosis via synergistic repression of SLC7A11. Cancer Discov 9(12):1673–1685

    CAS  PubMed  PubMed Central  Google Scholar 

  • Li J, Fang R, Wu J, Si Y, Bai J, Wang Q (2022) The NOP14 nucleolar protein suppresses the function and stemness of melanoma stem-like cells through Wnt/beta-catenin signaling inactivation. Bioengineered 13(3):7648–7658

    CAS  PubMed  PubMed Central  Google Scholar 

  • Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P (2015) The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst 1(6):417–425

    CAS  PubMed  PubMed Central  Google Scholar 

  • LIGHT sensitizes IFNγ–mediated apoptosis of HT-29 human carcinoma cells through both death receptor and mitochondria pathways | Cell Research [Internet]. [cited 2023 May 28]. Available from: https://www.nature.com/articles/7290210

  • Liu X, Nie L, Zhang Y, Yan Y, Wang C, Colic M et al (2023) Actin cytoskeleton vulnerability to disulfide stress mediates disulfidptosis. Nat Cell Biol 25(3):404–414

    CAS  PubMed  Google Scholar 

  • Morabito S, Reese F, Rahimzadeh N, Miyoshi E, Swarup V. High dimensional co-expression networks enable discovery of transcriptomic drivers in complex biological systems [Internet]. bioRxiv; 2022 [cited 2023 May 27]. p. 2022.09.22.509094. Available from: https://www.biorxiv.org/content/https://doi.org/10.1101/2022.09.22.509094v1

  • Nguyen LT, Ohashi PS (2015) Clinical blockade of PD1 and LAG3–potential mechanisms of action. Nat Rev Immunol 15(1):45–56

    CAS  PubMed  Google Scholar 

  • Pal B, Chen Y, Vaillant F, Capaldo BD, Joyce R, Song X et al (2021) A single-cell RNA expression atlas of normal, preneoplastic and tumorigenic states in the human breast. EMBO J 40(11):e107333

    CAS  PubMed  PubMed Central  Google Scholar 

  • Peng F, Liao M, Qin R, Zhu S, Peng C, Fu L et al (2022) Regulated cell death (RCD) in cancer: key pathways and targeted therapies. Signal Transduct Target Ther 7(1):286

    CAS  PubMed  PubMed Central  Google Scholar 

  • Quistgaard EM (2021) BAP31: Physiological functions and roles in disease. Biochimie 186:105–129

    CAS  PubMed  Google Scholar 

  • Rothlin CV, Hille TD, Ghosh S (2021) Determining the effector response to cell death. Nat Rev Immunol 21(5):292–304

    CAS  PubMed  Google Scholar 

  • Signatures of T cell dysfunction and exclusion predict cancer immunotherapy response | Nature Medicine [Internet]. [cited 2023 May 28]. Available from: https://www.nature.com/articles/s41591-018-0136-1

  • Sun C, Mezzadra R, Schumacher TN (2018) Regulation and function of the PD-L1 checkpoint. Immunity 48(3):434–452

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A et al (2021) Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71(3):209–249

    PubMed  Google Scholar 

  • Tan G, Lin C, Huang C, Chen B, Chen J, Shi Y et al (2022) Radiosensitivity of colorectal cancer and radiation-induced gut damages are regulated by gasdermin E. Cancer Lett 529:1–10

    CAS  PubMed  Google Scholar 

  • Tang R, Xu J, Zhang B, Liu J, Liang C, Hua J et al (2020) Ferroptosis, necroptosis, and pyroptosis in anticancer immunity. J Hematol OncolJ Hematol Oncol 13(1):110

    Google Scholar 

  • Topalian SL, Taube JM, Anders RA, Pardoll DM (2016) Mechanism-driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 16(5):275–287

    CAS  PubMed  PubMed Central  Google Scholar 

  • Tuit S, Salvagno C, Kapellos TS, Hau CS, Seep L, Oestreich M et al (2019) Transcriptional signature derived from murine tumor-associated macrophages correlates with poor outcome in breast cancer patients. Cell Rep 29(5):1221-1235.e5

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ugolini A, Tyurin VA, Tyurina YY, Tcyganov EN, Donthireddy L, Kagan VE et al (2020) Polymorphonuclear myeloid-derived suppressor cells limit antigen cross-presentation by dendritic cells in cancer. JCI Insight. 5(15):e138581

    PubMed  PubMed Central  Google Scholar 

  • Van Allen EM, Miao D, Schilling B, Shukla SA, Blank C, Zimmer L et al (2015) Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350(6257):207–211

    PubMed  PubMed Central  Google Scholar 

  • Wagner DL, Fritsche E, Pulsipher MA, Ahmed N, Hamieh M, Hegde M et al (2021) Immunogenicity of CAR T cells in cancer therapy. Nat Rev Clin Oncol 18(6):379–393

    PubMed  PubMed Central  Google Scholar 

  • Wang Q, Wang Y, Ding J, Wang C, Zhou X, Gao W et al (2020) A bioorthogonal system reveals antitumour immune function of pyroptosis. Nature 579(7799):421–426

    CAS  PubMed  Google Scholar 

  • Wei SC, Duffy CR, Allison JP (2018) Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov 8(9):1069–1086

    PubMed  Google Scholar 

  • Winer EP, Lipatov O, Im SA, Goncalves A, Muñoz-Couselo E, Lee KS et al (2021) Pembrolizumab versus investigator-choice chemotherapy for metastatic triple-negative breast cancer (KEYNOTE-119): a randomised, open-label, phase 3 trial. Lancet Oncol 22(4):499–511

    CAS  PubMed  Google Scholar 

  • Wu SZ, Al-Eryani G, Roden DL, Junankar S, Harvey K, Andersson A et al (2021) A single-cell and spatially resolved atlas of human breast cancers. Nat Genet 53(9):1334–1347

    CAS  PubMed  PubMed Central  Google Scholar 

  • Xi G, Gao J, Wan B, Zhan P, Xu W, Lv T et al (2019) GSDMD is required for effector CD8+ T cell responses to lung cancer cells. Int Immunopharmacol 74:105713

    CAS  PubMed  Google Scholar 

  • Xia H, Wang W, Crespo J, Kryczek I, Li W, Wei S et al (2017) Suppression of FIP200 and autophagy by tumor-derived lactate promotes naïve T cell apoptosis and affects tumor immunity. Sci Immunol. https://doi.org/10.1126/sciimmunol.aan4631

    Article  PubMed  PubMed Central  Google Scholar 

  • Xu C, Sun S, Johnson T, Qi R, Zhang S, Zhang J et al (2021) The glutathione peroxidase Gpx4 prevents lipid peroxidation and ferroptosis to sustain Treg cell activation and suppression of antitumor immunity. Cell Rep 35(11):109235

    CAS  PubMed  Google Scholar 

  • Yu G, Wang LG, Han Y, He QY (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. Omics J Integr Biol 16(5):284–287

    CAS  Google Scholar 

  • Zhang M, Guo R, Zhai Y, Yang D (2003) LIGHT sensitizes IFNγ-mediated apoptosis of MDA-MB-231 breast cancer cells leading to down-regulation of anti-apoptosis Bcl-2 family members. Cancer Lett 195(2):201–210

    CAS  PubMed  Google Scholar 

  • Zhang Y, Chen H, Mo H, Hu X, Gao R, Zhao Y et al (2021) Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer. Cancer Cell 39(12):1578-1593.e8

    CAS  PubMed  Google Scholar 

  • Zhu X, Jia W, Yan Y, Huang Y, Wang B. NOP14 regulates the growth, migration, and invasion of colorectal cancer cells by modulating the NRIP1/GSK-3β/β-catenin signaling pathway. Eur J Histochem [Internet]. 2021 Jul 2 [cited 2023 May 21];65(3). Available from: https://www.ejh.it/index.php/ejh/article/view/3246

Download references

Funding

This study was supported by the Foundation of Liaoning Province Education Administration (No. LJKZ0849).

Author information

Authors and Affiliations

  1. Department of Epidemiology and Health Statistics, Dalian Medical University, Dalian, China

    Yongxing Chen, Chenxin Jin, Jiaxue Cui, Yizhuo Diao, Ruiqi Wang, Rongxuan Xu, Zhihan Yao, Wei Wu & Xiaofeng Li

Authors
  1. Yongxing Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chenxin Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jiaxue Cui
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yizhuo Diao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ruiqi Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rongxuan Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Zhihan Yao
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Wei Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiaofeng Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

YX: original manuscript preparation, methods, and data curation. CX and JX: manuscript review and editing. YZ, RQ, RX, ZH and WW: software analysis. And study supervision: XF. All authors have read and approved the final version submitted.

Corresponding author

Correspondence to Xiaofeng Li.

Ethics declarations

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (XLS 37 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, Y., Jin, C., Cui, J. et al. Single-cell sequencing and bulk RNA data reveal the tumor microenvironment infiltration characteristics of disulfidptosis related genes in breast cancer. J Cancer Res Clin Oncol 149, 12145–12164 (2023). https://doi.org/10.1007/s00432-023-05109-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-023-05109-y

Keywords

Search

Navigation