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:

Stromal nicotinamide N-methyltransferase orchestrates the crosstalk between fibroblasts and tumour cells in oral squamous cell carcinoma: evidence from patient-derived assembled organoids

Oncogene volume 42, pages 1166–1180 (2023)Cite this article

Subjects

Abstract

Nicotinamide N-methyltransferase (NNMT) has been reported to be linked to methylation reprogramming in cancer cells. However, the role of NNMT in the tumour microenvironment (TME) remains elusive. Here, we found that the expression of NNMT was elevated in the stroma of oral squamous cell carcinoma (OSCC). Using a fibroblast-attached organoids (FAOs) model, we confirmed that stromal NNMT expression contributed to the generation of assembled tumour organoids. In a tumour regeneration assay with co-implanted OSCC cells and cancer-associated fibroblasts (CAFs), the tumour-initiating activity was reduced when NNMT was silenced in CAFs. In contrast, overexpression of NNMT in paracancerous fibroblasts (PFs) accelerated tumour growth in co-inoculation experiments. Notably, fibroblast-specific NNMT can regulate type I collagen deposition in both FAOs and xenografts. Further investigations confirmed that the stromal NNMT-aggravated oncogenic activities were attenuated by treatment with inhibitors of either collagen synthesis (e.g. losartan, tranilast, and halofuginone) in fibroblasts, or the focal adhesion kinase (FAK) signal (i.e. defactinib) in cancer cells. Mechanistically, overexpression of NNMT reduced the enrichment of H3K27me3 at the promoter of the gene encoding lysyl oxidase (LOX), a key enzyme that regulates the cross-linking of collagen I. Overall, we propose that the NNMT-LOX-FAK cascade contributes to the crosstalk between cancer cells and fibroblasts during OSCC development, and that NNMT-centric extracellular matrix remodelling is a novel therapeutic target for patients with OSCC.

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: Expression of NNMT is elevated in stromal compartment of OSCC-TME.
Fig. 2: Stromal NNMT expression is essential for the regeneration of FAOs.
Fig. 3: Stromal NNMT expression can promote the tumour-initiating activity of OSCC cells.
Fig. 4: Stromal NNMT can modulate the collagen deposition in OSCC-TME.
Fig. 5: Collagen deposition is involved in the stromal NNMT-aggravated oncogenic activities.
Fig. 6: Stromal NNMT promotes the cancer stenmess via sustaining FAK signal.
Fig. 7: NNMT promotes LOX transcription via receding the histone methylation.
Fig. 8: Schematic of the proposed CAF-cancer cross-talk mechanism.

Similar content being viewed by others

Data availability

The datasets used and analysed in the present study are available from the corresponding author on reasonable request. The datasets supporting the conclusions of this article are included within the article and its additional file.

References

  1. Hanahan D. Hallmarks of Cancer: New Dimensions. Cancer Discov. 2022;12:31–46.

    Article  CAS  PubMed  Google Scholar 

  2. Taniguchi S, Elhance A, Van Duzer A, Kumar S, Leitenberger JJ, Oshimori N. Tumor-initiating cells establish an IL-33-TGF-β niche signaling loop to promote cancer progression. Science. 2020;369:eaay1813.

    Article  CAS  PubMed  Google Scholar 

  3. Ostman A. The tumor microenvironment controls drug sensitivity. Nat Med. 2012;18:1332–4.

    Article  PubMed  Google Scholar 

  4. Plaks V, Kong N, Werb Z. The cancer stem cell niche: how essential is the niche in regulating stemness of tumor cells? Cell Stem Cell. 2015;16:225–38.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Hong S, Moreno-Navarrete JM, Wei X, Kikukawa Y, Tzameli I, Prasad D, et al. Nicotinamide N-methyltransferase regulates hepatic nutrient metabolism through Sirt1 protein stabilization. Nat Med. 2015;21:887–94.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Ulanovskaya OA, Zuhl AM, Cravatt BF. NNMT promotes epigenetic remodeling in cancer by creating a metabolic methylation sink. Nat Chem Biol. 2013;9:300–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Liu W, Gou H, Wang X, Li X, Hu X, Su H, et al. TTPAL promotes gastric tumorigenesis by directly targeting NNMT to activate PI3K/AKT signaling. Oncogene. 2021;40:6666–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Palanichamy K, Kanji S, Gordon N, Thirumoorthy K, Jacob JR, Litzenberg KT, et al. NNMT Silencing Activates Tumor Suppressor PP2A, Inactivates Oncogenic STKs, and Inhibits Tumor Forming Ability. Clin Cancer Res. 2017;23:2325–34.

    Article  CAS  PubMed  Google Scholar 

  9. Novak Kujundžić R, Prpić M, Đaković N, Dabelić N, Tomljanović M, Mojzeš A, et al. Nicotinamide N-Methyltransferase in Acquisition of Stem Cell Properties and Therapy Resistance in Cancer. Int J Mol Sci. 2021;22:5681.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Eckert MA, Coscia F, Chryplewicz A, Chang JW, Hernandez KM, Pan S, et al. Proteomics reveals NNMT as a master metabolic regulator of cancer-associated fibroblasts. Nature. 2019;569:723–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Puram SV, Tirosh I, Parikh AS, Patel AP, Yizhak K, Gillespie S, et al. Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer. Cell. 2017;171:1611–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Gandellini P, Andriani F, Merlino G, D’Aiuto F, Roz L, Callari M. Complexity in the tumour microenvironment: Cancer associated fibroblast gene expression patterns identify both common and unique features of tumour-stroma crosstalk across cancer types. Semin Cancer Biol. 2015;35:96–106.

    Article  CAS  PubMed  Google Scholar 

  13. 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;20:174–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Cox TR. The matrix in cancer. Nat Rev Cancer. 2021;21:217–38.

    Article  CAS  PubMed  Google Scholar 

  15. Mohan V, Das A, Sagi I. Emerging roles of ECM remodeling processes in cancer. Semin Cancer Biol. 2020;62:192–200.

    Article  CAS  PubMed  Google Scholar 

  16. Jolly LA, Novitskiy S, Owens P, Massoll N, Cheng N, Fang W, et al. Fibroblast-Mediated Collagen Remodeling Within the Tumor Microenvironment Facilitates Progression of Thyroid Cancers Driven by BrafV600E and Pten Loss. Cancer Res. 2016;76:1804–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Cox TR, Bird D, Baker AM, Barker HE, Ho MW, Lang G, et al. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res. 2013;73:1721–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Grasset EM, Bertero T, Bozec A, Friard J, Bourget I, Pisano S, et al. Matrix Stiffening and EGFR Cooperate to Promote the Collective Invasion of Cancer Cells. Cancer Res. 2018;78:5229–42.

    Article  CAS  PubMed  Google Scholar 

  19. Chen Y, Kim J, Yang S, Wang H, Wu CJ, Sugimoto H, et al. Type I collagen deletion in αSMA+ myofibroblasts augments immune suppression and accelerates progression of pancreatic cancer. Cancer Cell. 2021;39:548–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bhattacharjee S, Hamberger F, Ravichandra A, Miller M, Nair A, Affo S, et al. Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts. J Clin Investig. 2021;131:e146987.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Tuveson D, Clevers H. Cancer modeling meets human organoid technology. Science. 2019;364:952–5.

    Article  CAS  PubMed  Google Scholar 

  22. Hofer M, Lutolf MP. Engineering organoids. Nat Rev Mater. 2021;6:402–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. LeSavage BL, Suhar RA, Broguiere N, Lutolf MP, Heilshorn SC. Next-generation cancer organoids. Nat Mater. 2022;21:143–59.

    Article  CAS  PubMed  Google Scholar 

  24. Öhlund D, Handly-Santana A, Biffi G, Elyada E, Almeida AS, Ponz-Sarvise M, et al. Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. J Exp Med. 2017;214:579–96.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Kim E, Choi S, Kang B, Kong J, Kim Y, Yoon WH, et al. Creation of bladder assembloids mimicking tissue regeneration and cancer. Nature. 2020;588:664–9.

    Article  CAS  PubMed  Google Scholar 

  26. Zhao H, Jiang E, Shang Z. 3D Co-culture of Cancer-Associated Fibroblast with Oral Cancer Organoids. J Dent Res. 2021;100:201–8.

    Article  CAS  PubMed  Google Scholar 

  27. Chen X, Li R, Zhao H, Wang X, Shao Z, Shang Z. Phenotype transition of fibroblasts incorporated into patient-derived oral carcinoma organoids. Oral Dis. 2021. https://doi.org/10.1111/odi.14071.

  28. Lazard D, Sastre X, Frid MG, Glukhova MA, Thiery JP, Koteliansky VE. Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc Natl Acad Sci USA. 1993;90:999–1003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Gomez KE, Wu F, Keysar SB, Morton JJ, Miller B, Chimed TS, et al. Cancer Cell CD44 Mediates Macrophage/Monocyte-Driven Regulation of Head and Neck Cancer Stem Cells. Cancer Res. 2020;80:4185–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Li P, Chen T, Kuang P, Liu F, Li Z, Liu F, et al. Aurora-A/FOXO3A/SKP2 axis promotes tumor progression in clear cell renal cell carcinoma and dual-targeting Aurora-A/SKP2 shows synthetic lethality. Cell Death Dis. 2022;13:606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ding L, Fu Y, Zhu N, Zhao M, Ding Z, Zhang X, et al. OXTRHighstroma fibroblasts control the invasion pattern of oral squamous cell carcinoma via ERK5 signaling. Nat Commun. 2022;13:5124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Diop-Frimpong B, Chauhan VP, Krane S, Boucher Y, Jain RK. Losartan inhibits collagen I synthesis and improves the distribution and efficacy of nanotherapeutics in tumors. Proc Natl Acad Sci USA. 2011;108:2909–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ohta Y, Fujii M, Takahashi S, Takano A, Nanki K, Matano M, et al. Cell-matrix interface regulates dormancy in human colon cancer stem cells. Nature. 2022;608:784–94.

    Article  CAS  PubMed  Google Scholar 

  34. Chen Y, Zhao H, Liang W, Jiang E, Zhou X, Shao Z, et al. Autophagy regulates the cancer stem cell phenotype of head and neck squamous cell carcinoma through the noncanonical FOXO3/SOX2 axis. Oncogene. 2022;41:634–46.

    Article  CAS  PubMed  Google Scholar 

  35. Dawson JC, Serrels A, Stupack DG, Schlaepfer DD, Frame MC, Targeting FAK. in anticancer combination therapies. Nat Rev Cancer. 2021;21:313–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hamidi H, Ivaska J. Every step of the way: integrins in cancer progression and metastasis. Nat Rev Cancer. 2018;18:533–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Fan Z, Duan J, Wang L, Xiao S, Li L, Yan X, et al. PTK2 promotes cancer stem cell traits in hepatocellular carcinoma by activating Wnt/β-catenin signaling. Cancer Lett. 2019;450:132–43.

    Article  CAS  PubMed  Google Scholar 

  38. Fatherree JP, Guarin JR, McGinn RA, Naber SP, Oudin MJ. Chemotherapy-Induced Collagen IV Drives Cancer Cell Motility through Activation of Src and Focal Adhesion Kinase. Cancer Res. 2022;82:2031–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ricard-Blum S. The collagen family. Cold Spring Harb Perspect Biol. 2011;3:a004978.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Shoulders MD, Raines RT. Collagen structure and stability. Annu Rev Biochem. 2009;78:929–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Myllyharju J, Kivirikko KI. Collagens, modifying enzymes and their mutations in humans, flies and worms. Trends Genet. 2004;20:33–43.

    Article  CAS  PubMed  Google Scholar 

  42. Tran TQ, Lowman XH, Kong M. Molecular Pathways: Metabolic Control of Histone Methylation and Gene Expression in Cancer. Clin Cancer Res. 2017;23:4004–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Heinemann B, Nielsen JM, Hudlebusch HR, Lees MJ, Larsen DV, Boesen T, et al. Inhibition of demethylases by GSK-J1/J4. Nature. 2014;514:E1–2.

    Article  CAS  PubMed  Google Scholar 

  44. Hasegawa T, Yashiro M, Nishii T, Matsuoka J, Fuyuhiro Y, Morisaki T, et al. Cancer-associated fibroblasts might sustain the stemness of scirrhous gastric cancer cells via transforming growth factor-β signaling. Int J Cancer. 2014;134:1785–95.

    Article  CAS  PubMed  Google Scholar 

  45. Sharbeen G, McCarroll JA, Akerman A, Kopecky C, Youkhana J, Kokkinos J, et al. Cancer-Associated Fibroblasts in Pancreatic Ductal Adenocarcinoma Determine Response to SLC7A11 Inhibition. Cancer Res. 2021;81:3461–79.

    Article  CAS  PubMed  Google Scholar 

  46. Hu YB, Yan C, Mu L, Mi YL, Zhao H, Hu H, et al. Exosomal Wnt-induced dedifferentiation of colorectal cancer cells contributes to chemotherapy resistance. Oncogene. 2019;38:1951–65.

    Article  CAS  PubMed  Google Scholar 

  47. Seino T, Kawasaki S, Shimokawa M, Tamagawa H, Toshimitsu K, Fujii M, et al. Human Pancreatic Tumor Organoids Reveal Loss of Stem Cell Niche Factor Dependence during Disease Progression. Cell Stem Cell. 2018;22:454–67.

    Article  CAS  PubMed  Google Scholar 

  48. Jung J, Kim LJ, Wang X, Wu Q, Sanvoranart T, Hubert CG, et al. Nicotinamide metabolism regulates glioblastoma stem cell maintenance. JCI Insight. 2017;2:e90019.

    Article  PubMed  PubMed Central  Google Scholar 

  49. Kim J, Hong SJ, Lim EK, Yu YS, Kim SW, Roh JH, et al. Expression of nicotinamide N-methyltransferase in hepatocellular carcinoma is associated with poor prognosis. J Exp Clin Cancer Res. 2009;28:20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Wu M, Hu W, Wang G, Yao Y, Yu XF. Nicotinamide N-Methyltransferase Is a Prognostic Biomarker and Correlated With Immune Infiltrates in Gastric Cancer. Front Genet. 2020;11:580299.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Barker HE, Cox TR, Erler JT. The rationale for targeting the LOX family in cancer. Nat Rev Cancer. 2012;12:540–52.

    Article  CAS  PubMed  Google Scholar 

  52. Haj-Shomaly J, Vorontsova A, Barenholz-Cohen T, Levi-Galibov O, Devarasetty M, Timaner M, et al. T Cells Promote Metastasis by Regulating Extracellular Matrix Remodeling following Chemotherapy. Cancer Res. 2022;82:278–91.

    Article  CAS  PubMed  Google Scholar 

  53. Zhao H, Yan C, Hu Y, Mu L, Liu S, Huang K, et al. Differentiated cancer cell-originated lactate promotes the self-renewal of cancer stem cells in patient-derived colorectal cancer organoids. Cancer Lett. 2020;493:236–44.

    Article  CAS  PubMed  Google Scholar 

  54. Condello S, Sima L, Ivan C, Cardenas H, Schiltz G, Mishra RK, et al. Tissue Tranglutaminase Regulates Interactions between Ovarian Cancer Stem Cells and the Tumor Niche. Cancer Res. 2018;78:2990–3001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Luo X, Chen Y, Tang H, Wang H, Jiang E, Shao Z, et al. Melatonin inhibits EMT and PD-L1 expression through the ERK1/2/FOSL1 pathway and regulates anti-tumor immunity in HNSCC. Cancer Sci. 2022;113:2232–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Li X, Jiang E, Zhao H, Chen Y, Xu Y, Feng C, et al. Glycometabolic reprogramming-mediated proangiogenic phenotype enhancement of cancer-associated fibroblasts in oral squamous cell carcinoma: role of PGC-1α/PFKFB3 axis. Br J Cancer. 2022;127:449–61.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This study was supported by grants from National Key R&D Programme of China (No. 2022YFC2504200) and National Natural Science Foundation of China (Nos. 82273306, 81972547).

Author information

Author notes

  1. These authors contributed equally: Hui Zhao, Rui Li.

Authors and Affiliations

  1. The State Key Laboratory Breeding Base of Basic Science of Stomatology, Hubei Province & Key Laboratory of Oral Biomedicine (Wuhan University), Ministry of Education (Hubei-MOST KLOS & KLOBM), Wuhan, China

    Hui Zhao, Rui Li, Yang Chen, Xiao Yang & Zhengjun Shang

  2. Department of Oral and Maxillofacial-Head and Neck Oncology, School of Stomatology–Hospital of Stomatology, Wuhan University, Wuhan, China

    Hui Zhao & Zhengjun Shang

Authors
  1. Hui Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rui Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xiao Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zhengjun Shang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HZ and RL, conceived, designed, and conducted the research; YC and XY, analyzed the data; HZ and ZS, wrote the paper; ZS supervised the research.

Corresponding author

Correspondence to Zhengjun Shang.

Ethics declarations

Competing interests

The authors declare no competing interests.

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

Zhao, H., Li, R., Chen, Y. et al. Stromal nicotinamide N-methyltransferase orchestrates the crosstalk between fibroblasts and tumour cells in oral squamous cell carcinoma: evidence from patient-derived assembled organoids. Oncogene 42, 1166–1180 (2023). https://doi.org/10.1038/s41388-023-02642-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-023-02642-5

This article is cited by

Search

Advanced search

Quick links