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MAZ promotes tumor proliferation and immune evasion in lung adenocarcinoma

Oncogene volume 43, pages 3619–3632 (2024)Cite this article

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Abstract

Lung adenocarcinoma (LUAD) is the most dominant histological subtype of lung cancer and one of the most lethal malignancies. The identification of novel therapeutic targets is required for the treatment of LUAD. Here, we showed that MYC-associated zinc-finger protein (MAZ) is upregulated in LUAD tissues. MAZ expression levels are inversely correlated with patient survival. Silencing of MAZ decreased tumor proliferation and the expression of pro-tumorigenic chemokines and Galectin-9 (Gal-9), an immune checkpoint molecule. The pro-tumorigenic chemokines and Gal-9 induce immune suppression by recruitment of myeloid cells and inhibition of T cell activation, respectively. Mechanistically, MAZ transcriptionally regulates KRAS expression and activates its downstream AKT-NF-κB signaling pathway, which is crucial for tumor progression and immune evasion. Additionally, in vivo animal models and bioinformatic analyses indicated that MAZ suppression could enhance the efficacy of immune checkpoint blockade (ICB) therapy for LUAD. Overall, our results suggest that MAZ plays an important role in regulating cell proliferation and immune evasion via KRAS/AKT/NF-κB signaling in LUAD. Our findings offer a candidate molecular target for LUAD therapy, with implications for improving the efficacy of ICB therapy.

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Fig. 1: Elevated expression of MAZ in LUAD is associated with poor prognosis.
Fig. 2: Silencing of MAZ attenuates the proliferation of LUAD cells.
Fig. 3: MAZ regulates tumor growth by transcriptionally activating KRAS-AKT signaling.
Fig. 4: MAZ knockdown inhibits the expression of pro-tumorigenic chemokines.
Fig. 5: MAZ regulates the expression of Galectin-9 via KRAS/AKT/NF-κB signaling.
Fig. 6: MAZ facilitates tumor resistance against cytotoxic T cells through Galectin-9.
Fig. 7: MAZ inhibition in combination with ICB as a therapeutic strategy for LUAD.

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Data availability

The LUAD data from The Cancer Genome Atlas (TCGA) database, including the FPKM matrix and clinical information, were downloaded from UCSC Xena (http://xena.ucsc.edu/). The OAK and POPLAR RNA-seq data and relevant clinical information [47] were requested from Genentech at the European Genome-phenome Archive. The LUAD RNA-seq data for the Asian population (OncoSG cohort) [27] were downloaded from the website (https://src.gisapps.org/OncoSG/). The pre-immunotherapy RNA-seq data of non-small cell lung cancer (NSCLC) (GSE207422) were obtained from our previous study [33]. The CPTAC genomic (KRAS mutation status) and proteomic (protein matrix) data of LUAD from the supplementary tables of the paper reported by Michael et al. [48]. The raw RNA-seq data of A549-shCtrl and A549-shMAZ cells and CUT&TAG sequencing data of A549 cells were deposited in the Genome Sequence Archive in National Genomics Data Center, China National Center for Bioinformation/Beijing Institute of Genomics, Chinese Academy of Sciences (HRA007041), which is publicly accessible at https://ngdc.cncb.ac.cn/gsa-human/browse/HRA007041. The data generated in this study are available in the article and its supplementary files.

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: A Cancer J Clin. 2021;71:209–49.

    Google Scholar 

  2. Leiter A, Veluswamy RR, Wisnivesky JP. The global burden of lung cancer: current status and future trends. Nat Rev Clin Oncol. 2023;20:624–39.

    Article  PubMed  Google Scholar 

  3. Schabath MB, Cote ML. Cancer progress and priorities: lung cancer. Cancer Epidemiol, Biomark Prev. 2019;28:1563–79.

    Article  Google Scholar 

  4. Herbst RS, Morgensztern D, Boshoff C. The biology and management of non-small cell lung cancer. Nature. 2018;553:446–54.

    Article  CAS  PubMed  Google Scholar 

  5. Wang M, Herbst RS, Boshoff C. Toward personalized treatment approaches for non-small-cell lung cancer. Nat Med. 2021;27:1345–56.

    Article  CAS  PubMed  Google Scholar 

  6. Hanahan D. Hallmarks of cancer: new dimensions. Cancer Discov. 2022;12:31–46.

    Article  CAS  PubMed  Google Scholar 

  7. Zheng C, Wu H, Jin S, Li D, Tan S, Zhu X. Roles of Myc-associated zinc finger protein in malignant tumors. Asia-Pacific. J Clin Oncol. 2022;18:506–14.

    Google Scholar 

  8. Yang Q, Lang C, Wu Z, Dai Y, He S, Guo W, et al. MAZ promotes prostate cancer bone metastasis through transcriptionally activating the KRas-dependent RalGEFs pathway. J Exp Clin Cancer Res. 2019;38:391.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Wang X, Southard RC, Allred CD, Talbert DR, Wilson ME, Kilgore MW. MAZ drives tumor-specific expression of PPAR gamma 1 in breast cancer cells. Breast Cancer Res Treat. 2008;111:103–11.

    Article  CAS  PubMed  Google Scholar 

  10. van Weverwijk A, de Visser KE. Mechanisms driving the immunoregulatory function of cancer cells. Nat Rev Cancer. 2023;23:193–215.

    Article  PubMed  Google Scholar 

  11. Kalbasi A, Ribas A. Tumour-intrinsic resistance to immune checkpoint blockade. Nat Rev Immunol. 2020;20:25–39.

    Article  CAS  PubMed  Google Scholar 

  12. Wei CY, Zhu MX, Zhang PF, Huang XY, Wan JK, Yao XZ, et al. PKCα/ZFP64/CSF1 axis resets the tumor microenvironment and fuels anti-PD1 resistance in hepatocellular carcinoma. J Hepatol. 2022;77:163–76.

    Article  CAS  PubMed  Google Scholar 

  13. Ying H, Elpek KG, Vinjamoori A, Zimmerman SM, Chu GC, Yan H, et al. PTEN is a major tumor suppressor in pancreatic ductal adenocarcinoma and regulates an NF-κB-cytokine network. Cancer Discov. 2011;1:158–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Caetano MS, Zhang H, Cumpian AM, Gong L, Unver N, Ostrin EJ, et al. IL6 blockade reprograms the lung tumor microenvironment to limit the development and progression of K-ras-mutant lung cancer. Cancer Res. 2016;76:3189–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Yan R, Li J, Xiao Z, Fan X, Liu H, Xu Y, et al. DCLK1 suppresses tumor-specific cytotoxic T lymphocyte function through recruitment of MDSCs via the CXCL1-CXCR2 axis. Cell Mol Gastroenterol Hepatol. 2023;15:463–85.

    Article  CAS  PubMed  Google Scholar 

  16. Pittet MJ, Michielin O, Migliorini D. Clinical relevance of tumour-associated macrophages. Nat Rev Clin Oncol. 2022;19:402–21.

    Article  PubMed  Google Scholar 

  17. Yamaguchi H, Hsu JM, Yang WH, Hung MC. Mechanisms regulating PD-L1 expression in cancers and associated opportunities for novel small-molecule therapeutics. Nat Rev Clin Oncol. 2022;19:287–305.

    Article  CAS  PubMed  Google Scholar 

  18. Li Y, Jiang M, Aye L, Luo L, Zhang Y, Xu F, et al. UPP1 promotes lung adenocarcinoma progression through the induction of an immunosuppressive microenvironment. Nat Commun. 2024;15:1200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Coelho MA, de Carné Trécesson S, Rana S, Zecchin D, Moore C, Molina-Arcas M, et al. Oncogenic RAS signaling promotes tumor immunoresistance by stabilizing PD-L1 mRNA. Immunity. 2017;47:1083–1099.e1086.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Munn DH, Mellor AL. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol. 2016;37:193–207.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Liang F, Wang GZ, Wang Y, Yang YN, Wen ZS, Chen DN, et al. Tobacco carcinogen induces tryptophan metabolism and immune suppression via induction of indoleamine 2,3-dioxygenase 1. Signal Transduct Target Ther. 2022;7:311.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Yang R, Sun L, Li CF, Wang YH, Yao J, Li H, et al. Galectin-9 interacts with PD-1 and TIM-3 to regulate T cell death and is a target for cancer immunotherapy. Nat Commun. 2021;12:832.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sun Q, Hong Z, Zhang C, Wang L, Han Z, Ma D. Immune checkpoint therapy for solid tumours: clinical dilemmas and future trends. Signal Transduct Target Ther. 2023;8:320.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhu C, Anderson AC, Schubart A, Xiong H, Imitola J, Khoury SJ, et al. The Tim-3 ligand galectin-9 negatively regulates T helper type 1 immunity. Nat Immunol. 2005;6:1245–52.

    Article  CAS  PubMed  Google Scholar 

  25. Ni X, Wu W, Sun X, Ma J, Yu Z, He X, et al. Interrogating glioma-M2 macrophage interactions identifies Gal-9/Tim-3 as a viable target against PTEN-null glioblastoma. Sci Adv. 2022;8:eabl5165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Zheng S, Song J, Linghu D, Yang R, Liu B, Xue Z, et al. Galectin-9 blockade synergizes with ATM inhibition to induce potent anti-tumor immunity. Int J Biol Sci. 2023;19:981–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Chen J, Yang H, Teo ASM, Amer LB, Sherbaf FG, Tan CQ, et al. Genomic landscape of lung adenocarcinoma in East Asians. Nat Genet. 2020;52:177–86.

    Article  CAS  PubMed  Google Scholar 

  28. Liu T, Zhang L, Joo D, Sun SC. NF-κB signaling in inflammation. Signal Transduct Target Ther. 2017;2:17023.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Richmond A. Nf-kappa B, chemokine gene transcription and tumour growth. Nat Rev Immunol. 2002;2:664–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Taniguchi K, Karin M. NF-κB, inflammation, immunity and cancer: coming of age. Nat Rev Immunol. 2018;18:309–24.

    Article  CAS  PubMed  Google Scholar 

  31. Ozes ON, Mayo LD, Gustin JA, Pfeffer SR, Pfeffer LM, Donner DB. NF-kappaB activation by tumour necrosis factor requires the Akt serine-threonine kinase. Nature. 1999;401:82–85.

    Article  CAS  PubMed  Google Scholar 

  32. Hamarsheh S, Groß O, Brummer T, Zeiser R. Immune modulatory effects of oncogenic KRAS in cancer. Nat Commun. 2020;11:5439.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Hu J, Zhang L, Xia H, Yan Y, Zhu X, Sun F, et al. Tumor microenvironment remodeling after neoadjuvant immunotherapy in non-small cell lung cancer revealed by single-cell RNA sequencing. Genome Med. 2023;15:14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Mazieres J, Rittmeyer A, Gadgeel S, Hida T, Gandara DR, Cortinovis DL, et al. Atezolizumab versus docetaxel in pretreated patients with NSCLC: final results from the randomized phase 2 POPLAR and phase 3 OAK clinical trials. J Thorac Oncol. 2021;16:140–50.

    Article  CAS  PubMed  Google Scholar 

  35. Oeckinghaus A, Hayden MS, Ghosh S. Crosstalk in NF-κB signaling pathways. Nat Immunol. 2011;12:695–708.

    Article  CAS  PubMed  Google Scholar 

  36. Catanzaro JM, Sheshadri N, Pan JA, Sun Y, Shi C, Li J, et al. Oncogenic Ras induces inflammatory cytokine production by upregulating the squamous cell carcinoma antigens SerpinB3/B4. Nat Commun. 2014;5:3729.

    Article  CAS  PubMed  Google Scholar 

  37. Yang Z, Xu G, Wang B, Liu Y, Zhang L, Jing T, et al. USP12 downregulation orchestrates a protumourigenic microenvironment and enhances lung tumour resistance to PD-1 blockade. Nat Commun. 2021;12:4852.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Chen AY, Wolchok JD, Bass AR. TNF in the era of immune checkpoint inhibitors: friend or foe? Nat Rev Rheumatol. 2021;17:213–23.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Mercogliano MF, Bruni S, Mauro F, Elizalde PV, Schillaci R. Harnessing tumor necrosis factor alpha to achieve effective cancer immunotherapy. Cancers. 2021;13:564.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Xie M, Lin Z, Ji X, Luo X, Zhang Z, Sun M, et al. FGF19/FGFR4-mediated elevation of ETV4 facilitates hepatocellular carcinoma metastasis by upregulating PD-L1 and CCL2. J Hepatol. 2023;79:109–25.

    Article  CAS  PubMed  Google Scholar 

  41. Liu X, Tang R, Xu J, Tan Z, Liang C, Meng Q, et al. CRIP1 fosters MDSC trafficking and resets tumour microenvironment via facilitating NF-κB/p65 nuclear translocation in pancreatic ductal adenocarcinoma. Gut. 2023;72:2329–43.

    Article  CAS  PubMed  Google Scholar 

  42. Bianchi A, De Castro Silva I, Deshpande NU, Singh S, Mehra S, Garrido VT, et al. Cell-autonomous Cxcl1 sustains tolerogenic circuitries and stromal inflammation via neutrophil-derived TNF in pancreatic cancer. Cancer Discov. 2023;13:1428–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Hu H, Cheng R, Wang Y, Wang X, Wu J, Kong Y, et al. Oncogenic KRAS signaling drives evasion of innate immune surveillance in lung adenocarcinoma by activating CD47. J Clin Invest. 2023;133:e153470.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Mugarza E, van Maldegem F, Boumelha J, Moore C, Rana S, Llorian Sopena M, et al. Therapeutic KRAS(G12C) inhibition drives effective interferon-mediated antitumor immunity in immunogenic lung cancers. Sci Adv. 2022;8:eabm8780.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Liao W, Overman MJ, Boutin AT, Shang X, Zhao D, Dey P, et al. KRAS-IRF2 axis drives immune suppression and immune therapy resistance in colorectal cancer. Cancer Cell. 2019;35:559–572.e557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Li F, Huang Q, Luster TA, Hu H, Zhang H, Ng WL, et al. In vivo epigenetic CRISPR screen identifies Asf1a as an immunotherapeutic target in kras-mutant lung adenocarcinoma. Cancer Discov. 2020;10:270–87.

    Article  PubMed  Google Scholar 

  47. Patil NS, Nabet BY, Müller S, Koeppen H, Zou W, Giltnane J, et al. Intratumoral plasma cells predict outcomes to PD-L1 blockade in non-small cell lung cancer. Cancer cell. 2022;40:289–300.e284.

    Article  CAS  PubMed  Google Scholar 

  48. Gillette MA, Satpathy S, Cao S, Dhanasekaran SM, Vasaikar SV, Krug K, et al. Proteogenomic characterization reveals therapeutic vulnerabilities in lung adenocarcinoma. Cell. 2020;182:200–225.e235.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We acknowledge Professor Hongbin Ji of the Chinese Academy of Sciences for providing the mouse KP cell line.

Funding

This research was supported by the National Natural Science Foundation of China (Grant No. 82125001, 82201948), Innovation Program of Shanghai Municipal Education Commission (Grant No. 2023ZKZD33), and the Foundation of Shanghai Pulmonary Hospital (Grant No. FKLY20004, FKYQ2308, FKCX2304).

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  1. These authors contributed equally: Yan Chen, Xinsheng Zhu, Jue Wang, Junjie Hu.

Authors and Affiliations

  1. Department of Thoracic Surgery, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China

    Yan Chen, Xinsheng Zhu, Jue Wang, Junjie Hu, Jing Zhang, Xun Zhang, Lu Han, Ke Fei & Peng Zhang

  2. Experimental Animal Center, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China

    Huansha Yu

  3. Central Laboratory, Shanghai Pulmonary Hospital, School of Medicine, Tongji University, Shanghai, 200433, China

    Haiyang Hu & Lele Zhang

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Contributions

Yan Chen, Junjie Hu and Lele Zhang developed ideas and drafted the manuscript. Yan Chen, Jue Wang, Junjie Hu, and Xinsheng Zhu conducted the experiments and contributed to the analysis of data. Jing Zhang, Xun Zhang, Lu Han, Huansha Yu and Haiyang Hu contributed to the analysis of data. Lele Zhang, Peng Zhang, and Ke Fei supervised this study and edited the manuscript. All authors contributed to revising the manuscript and approved the final version for publication.

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Correspondence to Ke Fei, Peng Zhang or Lele Zhang.

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All procedures involving human samples were approved by the Ethics Committee of Shanghai Pulmonary Hospital (Project number: K23-309) and performed in accordance with the ethical standards. Animal experiments were conducted under the protocols approved by the Institutional Animal Care and Use Committee of Shanghai Pulmonary Hospital (Project number: K24-002), and the animals were raised in compliance with animal welfare regulations. We confirm that all methods were performed in accordance with the relevant guidelines and regulations, and informed consent was obtained from all participants. Written informed consent for the publication of identifiable images was also obtained from the human research participants.

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Chen, Y., Zhu, X., Wang, J. et al. MAZ promotes tumor proliferation and immune evasion in lung adenocarcinoma. Oncogene 43, 3619–3632 (2024). https://doi.org/10.1038/s41388-024-03194-y

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