Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

Phosphoglycerate mutase 1 promotes breast cancer progression through inducing immunosuppressive M2 macrophages

Cancer Gene Therapy (2024)Cite this article

Subjects

Abstract

Immunosuppressive tumor microenvironment (TME) contributes to tumor progression and causes major obstacles for cancer therapy. Phosphoglycerate mutase 1 (PGAM1) is a key enzyme involved in cancer metabolism while its role in remodeling TME remains unclear. In this study, we reported that PGAM1 suppression in breast cancer (BC) cells led to a decrease in M2 polarization, migration, and interleukin-10 (IL-10) production of macrophages. PGAM1 regulation on CCL2 expression was essential to macrophage recruitment, which further mediated by activating JAK-STAT pathway. Additionally, the CCL2/CCR2 axis was observed to participate in PGAM1-mediated immunosuppression via regulating PD-1 expression in macrophages. Combined targeting of PGAM1 and the CCL2/CCR2 axis led to a reduction in tumor growth in vivo. Furthermore, clinical validation in BC tissues indicated a positive correlation between PGAM1, CCL2 and macrophage infiltration. Our study provides novel insights into the induction of immunosuppressive TME by PGAM1 and propose a new strategy for combination therapies targeting PGAM1 and macrophages in BC.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Knockdown of PGAM1 impedes BC growth and reduces M2 macrophages in the TME.
Fig. 2: PGAM1 suppression in BC cells modulates macrophage function in vitro.
Fig. 3: PGAM1 suppression downregulates CCL2 expression and production in BC cells.
Fig. 4: PGAM1 regulates CCL2 production in BC cells through the STAT3 pathway.
Fig. 5: CCL2/CCR2/PD-1 axis in macrophages participates in PGAM1-mediated immunosuppression in TME.
Fig. 6: Targeting PGAM1 and CCL2/CCR2 macrophage axis reverses immunosuppressive TME and tumor growth in vivo.
Fig. 7: PGAM1 exhibits a positive correlation with CCL2 and macrophage infiltration in TME and is related to poor prognosis in patients with BC.

Similar content being viewed by others

Data availability

Relevant data are presented in the manuscript. Requests for data, experimental protocols, or any other questions can be made available to or qiansun@tmu.edu.cn or sunqian923@126.com.

References

  1. 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. CA Cancer J Clin. 2021;71:209–49.

    Article  PubMed  Google Scholar 

  2. DeSantis CE, Ma J, Gaudet MM, Newman LA, Miller KD, Goding Sauer A, et al. Breast cancer statistics, 2019. CA Cancer J Clin. 2019;69:438–51.

    Article  PubMed  Google Scholar 

  3. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33.

    Article  PubMed  Google Scholar 

  4. Miller KD, Nogueira L, Devasia T, Mariotto AB, Yabroff KR, Jemal A, et al. Cancer treatment and survivorship statistics, 2022. CA Cancer J Clin. 2022;72:409–36.

    Article  PubMed  Google Scholar 

  5. Danenberg E, Bardwell H, Zanotelli V, Provenzano E, Chin SF, Rueda OM, et al. Breast tumor microenvironment structures are associated with genomic features and clinical outcome. Nat Genet. 2022;54:660–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Hitosugi T, Zhou L, Elf S, Fan J, Kang HB, Seo JH, et al. Phosphoglycerate mutase 1 coordinates glycolysis and biosynthesis to promote tumor growth. Cancer Cell. 2012;22:585–600.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wen CL, Huang K, Jiang LL, Lu XX, Dai YT, Shi MM, et al. An allosteric PGAM1 inhibitor effectively suppresses pancreatic ductal adenocarcinoma. Proc Natl Acad Sci USA. 2019;116:23264–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Huang K, Liang Q, Zhou Y, Jiang LL, Gu WM, Luo MY, et al. A novel allosteric inhibitor of phosphoglycerate mutase 1 suppresses growth and metastasis of non-small-cell lung cancer. Cell Metab. 2021;33:223.

    Article  CAS  PubMed  Google Scholar 

  9. Ren F, Wu H, Lei Y, Zhang H, Liu R, Zhao Y, et al. Quantitative proteomics identification of phosphoglycerate mutase 1 as a novel therapeutic target in hepatocellular carcinoma. Mol Cancer. 2010;9:81.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Li C, Shu F, Lei B, Lv D, Zhang S, Mao X. Expression of PGAM1 in renal clear cell carcinoma and its clinical significance. Int J Clin Exp Pathol. 2015;8:9410–5.

    PubMed  PubMed Central  Google Scholar 

  11. Gao H, Yu B, Yan Y, Shen J, Zhao S, Zhu J, et al. Correlation of expression levels of ANXA2, PGAM1, and CALR with glioma grade and prognosis. J Neurosurg. 2013;118:846–53.

    Article  CAS  PubMed  Google Scholar 

  12. Sun Q, Li S, Wang Y, Peng H, Zhang X, Zheng Y, et al. Phosphoglyceric acid mutase-1 contributes to oncogenic mTOR-mediated tumor growth and confers non-small cell lung cancer patients with poor prognosis. Cell Death Differ. 2018;25:1160–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hinshaw DC, Shevde LA. The tumor microenvironment innately modulates cancer progression. Cancer Res. 2019;79:4557–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Vitale I, Manic G, Coussens LM, Kroemer G, Galluzzi L. Macrophages and metabolism in the tumor microenvironment. Cell Metab. 2019;30:36–50.

    Article  CAS  PubMed  Google Scholar 

  15. Chanmee T, Ontong P, Konno K, Itano N. Tumor-associated macrophages as major players in the tumor microenvironment. Cancers (Basel). 2014;6:1670–90.

    Article  PubMed  Google Scholar 

  16. Locati M, Curtale G, Mantovani A. Diversity, mechanisms, and significance of macrophage plasticity. Annu Rev Pathol. 2020;15:123–47.

    Article  CAS  PubMed  Google Scholar 

  17. Cha YJ, Koo JS. Role of tumor-associated myeloid cells in breast cancer. Cells. 2020;9:1785.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Guerriero JL. Macrophages: The road less traveled, changing anticancer therapy. Trends Mol Med. 2018;24:472–89.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kao KC, Vilbois S, Tsai CH, Ho PC. Metabolic communication in the tumour-immune microenvironment. Nat Cell Biol. 2022;24:1574–83.

    Article  CAS  PubMed  Google Scholar 

  20. Dey P, Kimmelman AC, DePinho RA. Metabolic codependencies in the tumor microenvironment. Cancer Discov. 2021;11:1067–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hou PP, Luo LJ, Chen HZ, Chen QT, Bian XL, Wu SF, et al. Ectosomal PKM2 promotes HCC by inducing macrophage differentiation and remodeling the tumor microenvironment. Mol Cell. 2020;78:1192–206.

    Article  CAS  PubMed  Google Scholar 

  22. Chen M, Liu H, Li Z, Ming AL, Chen H. Mechanism of PKM2 affecting cancer immunity and metabolism in tumor microenvironment. J Cancer. 2021;12:3566–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Serganova I, Cohen IJ, Vemuri K, Shindo M, Maeda M, Mane M, et al. LDH-A regulates the tumor microenvironment via HIF-signaling and modulates the immune response. PLoS One. 2018;13:e0203965.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Liu M, Li R, Wang M, Liu T, Zhou Q, Zhang D, et al. PGAM1 regulation of ASS1 contributes to the progression of breast cancer through the cAMP/AMPK/CEBPB pathway. Mol Oncol. 2022;16:2843–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gordon SR, Maute RL, Dulken BW, Hutter G, George BM, McCracken MN, et al. PD-1 expression by tumour-associated macrophages inhibits phagocytosis and tumour immunity. Nature. 2017;545:495–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Vander Heiden MG, Cantley LC, Thompson CB. Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science. 2009;324:1029–33.

    Article  Google Scholar 

  27. Zeng X, Li Z, Zhu C, Xu L, Sun Y, Han S. Research progress of nanocarriers for gene therapy targeting abnormal glucose and lipid metabolism in tumors. Drug Deliv. 2021;28:2329–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Batra S, Adekola KU, Rosen ST, Shanmugam M. Cancer metabolism as a therapeutic target. Oncology (Williston Park). 2013;27:460–7.

    PubMed  Google Scholar 

  29. Vander Heiden MG, Locasale JW, Swanson KD, Sharfi H, Heffron GJ, Amador-Noguez D, et al. Evidence for an alternative glycolytic pathway in rapidly proliferating cells. Science. 2010;329:1492–9.

    Article  PubMed Central  Google Scholar 

  30. Jiang X, Sun Q, Li H, Li K, Ren X. The role of phosphoglycerate mutase 1 in tumor aerobic glycolysis and its potential therapeutic implications. Int J Cancer. 2014;135:1991–6.

    Article  CAS  PubMed  Google Scholar 

  31. Liu X, Weng Y, Liu P, Sui Z, Zhou L, Huang Y, et al. Identification of PGAM1 as a putative therapeutic target for pancreatic ductal adenocarcinoma metastasis using quantitative proteomics. Onco Targets Ther. 2018;11:3345–57.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Liu X, Tan X, Liu P, Wu Y, Qian S, Zhang X. Phosphoglycerate mutase 1 (PGAM1) promotes pancreatic ductal adenocarcinoma (PDAC) metastasis by acting as a novel downstream target of the PI3K/Akt/mTOR pathway. Oncol Res. 2018;26:1123–31.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zhang D, Jin N, Sun W, Li X, Liu B, Xie Z, et al. Phosphoglycerate mutase 1 promotes cancer cell migration independent of its metabolic activity. Oncogene. 2017;36:2900–9.

    Article  CAS  PubMed  Google Scholar 

  34. Ajuebor MN, Flower RJ, Hannon R, Christie M, Bowers K, Verity A, et al. Endogenous monocyte chemoattractant protein-1 recruits monocytes in the zymosan peritonitis model. J Leukoc Biol. 1998;63:108–16.

    Article  CAS  PubMed  Google Scholar 

  35. Weber KS, von Hundelshausen P, Clark-Lewis I, Weber PC, Weber C. Differential immobilization and hierarchical involvement of chemokines in monocyte arrest and transmigration on inflamed endothelium in shear flow. Eur J Immunol. 1999;29:700–12.

    Article  CAS  PubMed  Google Scholar 

  36. Roca H, Varsos ZS, Sud S, Craig MJ, Ying C, Pienta KJ. CCL2 and interleukin-6 promote survival of human CD11b+ peripheral blood mononuclear cells and induce M2-type macrophage polarization. J Biol Chem. 2009;284:34342–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. O’Hayre M, Salanga CL, Handel TM, Allen SJ. Chemokines and cancer: migration, intracellular signalling and intercellular communication in the microenvironment. Biochem J. 2008;409:635–49.

    Article  PubMed  Google Scholar 

  38. Chen C, He W, Huang J, Wang B, Li H, Cai Q, et al. LNMAT1 promotes lymphatic metastasis of bladder cancer via CCL2 dependent macrophage recruitment. Nat Commun. 2018;9:3826.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Qian BZ, Li J, Zhang H, Kitamura T, Zhang J, Campion LR, et al. CCL2 recruits inflammatory monocytes to facilitate breast-tumour metastasis. Nature. 2011;475:222–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Li X, Yao W, Yuan Y, Chen P, Li B, Li J, et al. Targeting of tumour-infiltrating macrophages via CCL2/CCR2 signalling as a therapeutic strategy against hepatocellular carcinoma. Gut. 2017;66:157–67.

    Article  CAS  PubMed  Google Scholar 

  41. Shen H, He M, Lin R, Zhan M, Xu S, Huang X, et al. PLEK2 promotes gallbladder cancer invasion and metastasis through EGFR/CCL2 pathway. J Exp Clin Cancer Res. 2019;38:247.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Zhang J, Yan Y, Cui X, Zhang J, Yang Y, Li H, et al. CCL2 expression correlates with snail expression and affects the prognosis of patients with gastric cancer. Pathol Res Pract. 2017;213:217–21.

    Article  CAS  PubMed  Google Scholar 

  43. Fein MR, He XY, Almeida AS, Bružas E, Pommier A, Yan R, et al. Cancer cell CCR2 orchestrates suppression of the adaptive immune response. J Exp Med. 2020;217:e20181551.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Kadomoto S, Izumi K, Mizokami A. Roles of CCL2-CCR2 axis in the tumor microenvironment. Int J Mol Sci. 2021;22:8530.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Miyamoto T, Murakami R, Hamanishi J, Tanigaki K, Hosoe Y, Mise N, et al. B7-H3 suppresses antitumor immunity via the CCL2-CCR2-M2 macrophage axis and contributes to ovarian cancer progression. Cancer Immunol Res. 2022;10:56–69.

    Article  CAS  PubMed  Google Scholar 

  46. Hajal C, Shin Y, Li L, Serrano JC, Jacks T, Kamm RD. The CCL2-CCR2 astrocyte-cancer cell axis in tumor extravasation at the brain. Sci Adv. 2021;7:eabg8139.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Gabrilovich DI, Ostrand-Rosenberg S, Bronte V. Coordinated regulation of myeloid cells by tumours. Nat Rev Immunol. 2012;12:253–68.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Pathria P, Louis TL, Varner JA. Targeting tumor-associated macrophages in cancer. Trends Immunol. 2019;40:310–27.

    Article  CAS  PubMed  Google Scholar 

  49. Yang H, Zhang Q, Xu M, Wang L, Chen X, Feng Y, et al. CCL2-CCR2 axis recruits tumor associated macrophages to induce immune evasion through PD-1 signaling in esophageal carcinogenesis. Mol Cancer. 2020;19:41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Tu MM, Abdel-Hafiz HA, Jones RT, Jean A, Hoff KJ, Duex JE, et al. Inhibition of the CCL2 receptor, CCR2, enhances tumor response to immune checkpoint therapy. Commun Biol. 2020;3:720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank the tumor tissue banking facility of Tianjin Medical University Cancer Institute and Hospital for providing tissues from BC patients.

Funding

This study was supported by grants from the National Natural Science Foundation of China (82373283, 82372779, U20A20375).

Author information

Author notes

  1. These authors contributed equally: Dong Zhang, Min Wang.

Authors and Affiliations

  1. Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Tianjin, China

    Dong Zhang, Min Wang, Shiya Ma, Min Liu, Wenwen Yu, Xiying Zhang, Ting Liu, Shaochuan Liu, Xiubao Ren & Qian Sun

  2. Key Laboratory of Cancer Prevention and Therapy, Tianjin, China

    Dong Zhang, Min Wang, Shiya Ma, Min Liu, Wenwen Yu, Xiying Zhang, Ting Liu, Shaochuan Liu, Xiubao Ren & Qian Sun

  3. Tianjin’s Clinical Research Center for Cancer, Tianjin, China

    Dong Zhang, Min Wang, Shiya Ma, Min Liu, Wenwen Yu, Xiying Zhang, Ting Liu, Shaochuan Liu, Xiubao Ren & Qian Sun

  4. Key Laboratory of Cancer Immunology and Biotherapy, Tianjin, China

    Dong Zhang, Min Wang, Shiya Ma, Min Liu, Wenwen Yu, Xiying Zhang, Ting Liu, Shaochuan Liu, Xiubao Ren & Qian Sun

  5. Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education, Tianjin, China

    Dong Zhang, Min Wang, Shiya Ma, Min Liu, Wenwen Yu, Xiying Zhang, Ting Liu, Shaochuan Liu, Xiubao Ren & Qian Sun

  6. Department of Immunology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

    Dong Zhang, Min Wang, Shiya Ma, Min Liu, Wenwen Yu, Xiying Zhang, Ting Liu, Shaochuan Liu, Xiubao Ren & Qian Sun

  7. Department of Pathology, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

    Dong Zhang

  8. Department of Biotherapy, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China

    Xiubao Ren

Authors
  1. Dong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Min Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shiya Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Min Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Wenwen Yu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ting Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Shaochuan Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Xiubao Ren
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Qian Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Dong Zhang and Qian Sun conceptualized and designed the experiments, supervised the study, and reviewed the manuscript. Dong Zhang collected and analyzed the data and wrote the original draft. Min Wang, Siya Ma, and Min Liu were responsible for experimental performance and statistical analyses. Wenwen Yu, Ting Liu, and Xiying Zhang conducted experiments. Shaochuan Liu was responsible for the patient follow-up. Xiubao Ren provided the guidance and suggestions. All authors reviewed and approved the final version of the manuscript.

Corresponding author

Correspondence to Qian Sun.

Ethics declarations

Competing interests

The authors declare no competing interests.

Consent for publication

Not applicable.

Ethics approval and consent to participate

This study was approved by the Ethical Committee of Tianjin Medical University Cancer Institute and Hospital, and all patients signed the informed consent form. Animal experiments were performed in accordance with relevant guidelines and regulations, and were approved by the Animal Ethical and Welfare Committee of Tianjin Medical University Cancer Institute and Hospital (approval number: AEC2021015).

Additional information

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

Supplementary information

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

Zhang, D., Wang, M., Ma, S. et al. Phosphoglycerate mutase 1 promotes breast cancer progression through inducing immunosuppressive M2 macrophages. Cancer Gene Ther (2024). https://doi.org/10.1038/s41417-024-00769-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41417-024-00769-5

Search

Advanced search

Quick links