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:

Enhancer hijacking drives FAM20C expression to promote papillary thyroid cancer progression

Cancer Gene Therapy volume 32, pages 854–869 (2025)Cite this article

Subjects

Abstract

Papillary thyroid cancer (PTC) is the most common endocrine cancer, with a good prognosis in most cases. However, aggressive PTC can metastasise or reoccur and become refractory disease. Therefore, it’s urgent to uncover new biomarkers for aggressive PTC. Accumulating evidence suggests that aberrant enhancers and targeted gene transcription drive the progression of PTC. To identify the cancer-specific enhancers and their downstream genes in PTC, we profiled the transcriptomes (RNA-seq) and enhancer-based epigenomic reorganisation (ChIP-seq) of cancer tissues and matched normal tissues from three PTC patients. Importantly, six candidate genes (RHBDF1, FAM20C, PHLDA2, TMPRSS6, LAD1, and BGN) were identified to be consistently upregulated by enhancers in PTC and correlated with prognosis. Further experiments verified the function of enhancers governing FAM20C in regulating PTC tumorigenesis, thereby unveiling a FAM20C-governed oncogenic mechanism for suppressing two cytokines (TNF-α and TGF-β) in PTC. Additionally, we demonstrated that a FAM20C inhibitor (3r) suppressed the proliferation and invasion of thyroid cancer cells in vitro and vivo. Moreover, FAM20C is driven by KLF12 through its enhancer. Collectively, our study uncovers the potential correlations between the aberrant activation of cancer-specific enhancers and PTC tumorigenesis and identifies FAM20C as a novel target for PTC.

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

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to the full article PDF.

USD 39.95

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

Fig. 1: Enhancer landscape of papillary thyroid carcinoma (PTC).
Fig. 2: Transcriptome analysis of gene expression in PTC tissues and paired normal tissues.
Fig. 3: Identification of target genes that may be regulated by cancer-specific enhancers.
Fig. 4: Further screening for oncogenes was performed using The Cancer Genome Atlas (TCGA) database.
Fig. 5: FAM20C is an enhancer-driven gene.
Fig. 6: FAM20C knockdown inhibits thyroid cancer progression in vitro and in vivo.
Fig. 7: FAM20C knockdown activates the TNF signalling pathway while inhibiting the TGF-β signalling pathway in thyroid cancer.
Fig. 8: Antitumour effects of 3r in thyroid cancer cells.
Fig. 9: Transcription factor KLF12 increases FAM20C expression in PTC.

Similar content being viewed by others

Data availability

The ChIP-seq and RNA-seq data generated in this study have been deposited to the NCBI Gene Expression Omnibus (GEO) with the accession codes GSE224355, GSE224356 and Sequence Read Archive (SRA) under accession number PRJNA1070988. The corresponding author can provide all other data to support this study upon reasonable request. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

References

  1. Rossi ED, Pantanowitz L, Hornick JL. A worldwide journey of thyroid cancer incidence centred on tumour histology. Lancet Diabetes Endocrinol. 2021;9:193–4.

    Article  PubMed  Google Scholar 

  2. Ruan X, Shi X, Dong Q, Yu Y, Hou X, Song X, et al. Antitumor effects of anlotinib in thyroid cancer. Endocr Relat Cancer. 2019;26:153–64.

    Article  CAS  PubMed  Google Scholar 

  3. Du L, Zhao Z, Zheng R, Li H, Zhang S, Li R, et al. Epidemiology of thyroid cancer: incidence and mortality in China, 2015. Front Oncol. 2020;10:1702.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Schneider DF, Chen H. New developments in the diagnosis and treatment of thyroid cancer. CA Cancer J Clin. 2013;63:374–94.

    PubMed  Google Scholar 

  5. Ruan XH, Tian MR, Kang N, Ma WK, Zeng Y, Zhuang GJ, et al. Genome-wide identification of m6A-associated functional SNPs as potential functional variants for thyroid cancer. Am J Cancer Res. 2021;11:5402–14.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Hou XK, Shi XL, Zhang W, Li DP, Hu LF, Yang JH, et al. LDHA induces EMT gene transcription and regulates autophagy to promote the metastasis and tumorigenesis of papillary thyroid carcinoma. Cell Death Dis. 2021;12:347.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Toraih EA, Hussein MH, Zerfaoui M, Attia AS, Ellythy AM, Mostafa A, et al. Site-specific metastasis and survival in papillary thyroid cancer: the importance of brain and multi-organ disease. Cancers. 2021;13:1625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Brown AP, Chen J, Hitchcock YJ, Szabo A, Shrieve DC, Tward JD. The risk of second primary malignancies up to three decades after the treatment of differentiated thyroid cancer. J Clin Endocrinol Metab. 2008;93:504–15.

    Article  CAS  PubMed  Google Scholar 

  9. Xing MZ, Haugen BR, Schlumberger M. Progress in molecular-based management of differentiated thyroid cancer. Lancet. 2013;381:1058–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Fagin JA, Matsuo K, Karmakar A, Chen DL, Tang SH, Koeffler HP. High prevalence of mutations of the p53 gene in poorly differentiated human thyroid carcinomas. J Clin Invest. 1993;91:179–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Donghi R, Longoni A, Pilotti S, Michieli P, Della Porta G, Pierotti MA. Gene p53 mutations are restricted to poorly differentiated and undifferentiated carcinomas of the thyroid gland. J Clin Invest. 1993;91:1753–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Murugan AK, Xing M. Anaplastic thyroid cancers harbor novel oncogenic mutations of the ALK gene. Cancer Res. 2011;71:4403–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li S, Hu G, Chen Y, Sang Y, Tang Q, Liu R. TERT upstream promoter methylation regulates TERT expression and acts as a therapeutic target in TERT promoter mutation-negative thyroid cancer. Cancer Cell Int. 2024;24:271.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Liu R, Zhu G, Tan J, Shen X, Xing M. Genetic trio of BRAF and TERT alterations and rs2853669TT in papillary thyroid cancer aggressiveness. J Natl Cancer Inst. 2024;116:694–701.

    Article  CAS  PubMed  Google Scholar 

  15. Flavahan WA, Gaskell E, Bernstein BE. Epigenetic plasticity and the hallmarks of cancer. Science. 2017;357:eaal2380.

  16. Akhtar-Zaidi B, Cowper-Sal-lari R, Corradin O, Saiakhova A, Bartels CF, Balasubramanian D, et al. Epigenomic enhancer profiling defines a signature of colon cancer. Science. 2012;336:736–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Qamra A, Xing M, Padmanabhan N, Kwok JJT, Zhang S, Xu C, et al. Epigenomic promoter alterations amplify gene isoform and immunogenic diversity in gastric adenocarcinoma. Cancer Discov. 2017;7:630–51.

    Article  CAS  PubMed  Google Scholar 

  18. Yao X, Tan J, Lim KJ, Koh J, Ooi WF, Li Z, et al. VHL deficiency drives enhancer activation of oncogenes in clear cell renal cell carcinoma. Cancer Discov. 2017;7:1284–305.

    Article  CAS  PubMed  Google Scholar 

  19. Lomberk G, Dusetti N, Iovanna J, Urrutia R. Emerging epigenomic landscapes of pancreatic cancer in the era of precision medicine. Nat Commun. 2019;10:3875.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Tang F, Yang Z, Tan Y, Li Y. Super-enhancer function and its application in cancer targeted therapy. NPJ Precis Oncol. 2020;4:2.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Huang H, Hu J, Maryam A, Huang Q, Zhang Y, Ramakrishnan S, et al. Defining super-enhancer landscape in triple-negative breast cancer by multiomic profiling. Nat Commun. 2021;12:2242.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Ye B, Fan D, Xiong W, Li M, Yuan J, Jiang Q, et al. Oncogenic enhancers drive esophageal squamous cell carcinogenesis and metastasis. Nat Commun. 2021;12:4457.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kelly MR, Wisniewska K, Regner MJ, Lewis MW, Perreault AA, Davis ES, et al. A multi-omic dissection of super-enhancer driven oncogenic gene expression programs in ovarian cancer. Nat Commun. 2022;13:4247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Zhang L, Xiong D, Liu Q, Luo Y, Tian Y, Xiao X, et al. Genome-wide histone H3K27 acetylation profiling identified genes correlated with prognosis in papillary thyroid carcinoma. Front Cell Dev Biol. 2021;9:682561.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Cao XY, Dang L, Zheng XQ, Lu Y, Lu YM, Ji RJ, et al. Targeting super-enhancer-driven oncogenic transcription by CDK7 inhibition in anaplastic thyroid carcinoma. Thyroid. 2019;29:809–23.

    Article  CAS  PubMed  Google Scholar 

  26. Huang J, Liang X, Xuan Y, Geng C, Li Y, Lu H, et al. A reference human genome dataset of the BGISEQ-500 sequencer. Gigascience. 2017;6:1–9.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Chen Y, Chen Y, Shi C, Huang Z, Zhang Y, Li S, et al. SOAPnuke: a MapReduce acceleration-supported software for integrated quality control and preprocessing of high-throughput sequencing data. Gigascience. 2018;7:1–6.

    Article  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  29. Li R, Li Y, Kristiansen K, Wang J. SOAP: short oligonucleotide alignment program. Bioinformatics. 2008;24:713–4.

    Article  CAS  PubMed  Google Scholar 

  30. Zhang Y, Liu T, Meyer CA, Eeckhoute J, Johnson DS, Bernstein BE, et al. Model-based analysis of ChIP-Seq (MACS). Genome Biol. 2008;9:R137.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kramer A, Green J, Pollard J Jr, Tugendreich S. Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics. 2014;30:523–30.

    Article  PubMed  Google Scholar 

  32. Yokoyama Y, Zhu H, Lee JH, Kossenkov AV, Wu SY, Wickramasinghe JM, et al. BET inhibitors suppress ALDH activity by targeting ALDH1A1 super-enhancer in ovarian cancer. Cancer Res. 2016;76:6320–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Loven J, Hoke HA, Lin CY, Lau A, Orlando DA, Vakoc CR, et al. Selective inhibition of tumor oncogenes by disruption of super-enhancers. Cell. 2013;153:320–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yamane K, Ihn H, Asano Y, Jinnin M, Tamaki K. Antagonistic effects of TNF-alpha on TGF-beta signaling through down-regulation of TGF-beta receptor type II in human dermal fibroblasts. J Immunol. 2003;171:3855–62.

    Article  CAS  PubMed  Google Scholar 

  35. Szondy Z, Pallai A. Transmembrane TNF-alpha reverse signaling leading to TGF-beta production is selectively activated by TNF targeting molecules: therapeutic implications. Pharmacol Res. 2017;115:124–32.

    Article  CAS  PubMed  Google Scholar 

  36. Liu ZW, Zhang YM, Zhang LY, Zhou T, Li YY, Zhou GC, et al. Duality of interactions between TGF-beta and TNF-alpha during tumor formation. Front Immunol. 2021;12:810286.

    Article  CAS  PubMed  Google Scholar 

  37. Zhao RY, Fu LL, Yuan ZX, Liu Y, Zhang K, Chen YM, et al. Discovery of a novel small-molecule inhibitor of Fam20C that induces apoptosis and inhibits migration in triple negative breast cancer. Eur J Med Chem. 2021;210:113088.

    Article  CAS  PubMed  Google Scholar 

  38. Qin ZY, Wang PQ, Li XY, Zhang SY, Tian M, Dai Y, et al. Systematic network-based discovery of a Fam20C inhibitor (FL-1607) with apoptosis modulation in triple-negative breast cancer. Mol Biosyst. 2016;12:2108–18.

    Article  CAS  PubMed  Google Scholar 

  39. Tagliabracci VS, Engel JL, Wen JZ, Wiley SE, Worby CA, Kinch LN, et al. Secreted kinase phosphorylates extracellular proteins that regulate biomineralization. Science. 2012;336:1150–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ishikawa HO, Xu AG, Ogura E, Manning G, Irvine KD, The raine syndrome protein FAM20C is a golgi kinase that phosphorylates bio-mineralization proteins. PLoS ONE. 2012;7:e42988.

  41. Tagliabracci VS, Wiley SE, Guo X, Kinch LN, Durrant E, Wen JZ, et al. A single kinase generates the majority of the secreted phosphoproteome. Cell. 2015;161:1619–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Liu XP, Zhan YB, Xu WX, Liu XY, Geng YW, Liu LX, et al. Prognostic and immunological role of Fam20C in pan-cancer. Biosci Rep. 2021;41:Bsr20201920.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wu Y, Wang H, Liu C. From biomineralization to tumorogenesis-the expanding insight of the physiological and pathological roles of Fam20C. Biosci Rep. 2021;41:BSR20210040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Lin B, Jiang X, Bhandari A, Chen Q, Pan Y. FAM20C promotes papillary thyroid cancer proliferation and metastasis via epithelial-mesenchymal transition. Mol Carcinog. 2025;64:152–61.

    Article  CAS  PubMed  Google Scholar 

  45. Nakamura Y, Migita T, Hosoda F, Okada N, Gotoh M, Arai Y, et al. Krüppel-like factor 12 plays a significant role in poorly differentiated gastric cancer progression. Int J Cancer. 2009;125:1859–67.

    Article  CAS  PubMed  Google Scholar 

  46. Pan X, Zhang W, Wang L, Guo H, Zheng M, Wu H, et al. KLF12 transcriptionally regulates PD-L1 expression in non-small cell lung cancer. Mol Oncol. 2023;17:2659–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Plenchette S, Romagny S, Laurens V, Bettaieb A. S-Nitrosylation in TNF superfamily signaling pathway: implication in cancer. Redox Biol. 2015;6:507–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Wang X, Lin Y. Tumor necrosis factor and cancer, buddies or foes? Acta Pharm Sin. 2008;29:1275–88.

    Article  Google Scholar 

  49. Cruceriu D, Baldasici O, Balacescu O, Berindan-Neagoe I. The dual role of tumor necrosis factor-alpha (TNF-alpha) in breast cancer: molecular insights and therapeutic approaches. Cell Oncol. 2020;43:1–18.

    Article  CAS  Google Scholar 

  50. Bauerle KT, Schweppe RE, Haugen BR. Inhibition of nuclear factor-kappa B differentially affects thyroid cancer cell growth, apoptosis, and invasion. Mol Cancer. 2010;9:117.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Mitsiades N, Poulaki V, Tseleni-Balafouta S, Koutras DA, Stamenkovic I. Thyroid carcinoma cells are resistant to FAS-mediated apoptosis but sensitive to tumor necrosis factor-related apoptosis-inducing ligand. Cancer Res. 2000;60:4122–9.

    CAS  PubMed  Google Scholar 

  52. Pisarev MA, Thomasz L, Juvenal GJ. Role of transforming growth factor beta in the regulation of thyroid function and growth. Thyroid. 2009;19:881–92.

    Article  CAS  PubMed  Google Scholar 

  53. Zhi J, Zhang P, Zhang W, Ruan X, Tian M, Guo S, et al. Inhibition of BRAF sensitizes thyroid carcinoma to immunotherapy by enhancing tsMHCII-mediated immune recognition. J Clin Endocrinol Metab. 2021;106:91–107.

    Article  PubMed  Google Scholar 

  54. Dash S, Sahu AK, Srivastava A, Chowdhury R, Mukherjee S. Exploring the extensive crosstalk between the antagonistic cytokines- TGF-beta and TNF-alpha in regulating cancer pathogenesis. Cytokine. 2021;138:155348.

    Article  CAS  PubMed  Google Scholar 

  55. Kalliolias GD, Ivashkiv LB. TNF biology, pathogenic mechanisms and emerging therapeutic strategies. Nat Rev Rheumatol. 2016;12:49–62.

    Article  CAS  PubMed  Google Scholar 

  56. Nikiforov YE. Thyroid carcinoma: molecular pathways and therapeutic targets. Mod Pathol. 2008;21:S37–S43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Naoum GE, Morkos M, Kim B, Arafat W. Novel targeted therapies and immunotherapy for advanced thyroid cancers. Mol Cancer. 2018;17:51.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Hu LF, Zhang J, Tian MR, Kang N, Xu GW, Zhi JT, et al. Pharmacological inhibition of Ref-1 enhances the therapeutic sensitivity of papillary thyroid carcinoma to vemurafenib. Cell Death Dis. 2022;13:124.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Prof. Yupeng Chen (Tianjin Medical University) and Prof. Nan Qin (Tianjin Medical University) for generously providing technical support and helpful discussion and suggestions.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82172821, 82103386, 82272721, 82103234), Tianjin Municipal Science and Technology Project (19JCYBJC27400, 21JCZDJC00360), and Beijing-Tianjin-Hebei Basic Research Cooperation Project (20JCZXJC00120), The Science & Technology Development Fund of Tianjin Education Commission for Higher Education (2021ZD033), Tianjin Medical Key Discipline (Specialty) Construction Project (TJYXZDXK-058B), Tianjin Health Research Project (TJWJ2022XK024).

Author information

Author notes

  1. These authors contributed equally: Xianhui Ruan, Wei Zhang, Xiukun Hou.

Authors and Affiliations

  1. Department of Thyroid and Neck Tumor, Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin’s Clinical Research Center for Cancer, Tianjin, China

    Xianhui Ruan, Wei Zhang, Xiukun Hou, Guiming Fu, Weike Ma, Mengran Tian, Ming Gao, Dapeng Li & Xiangqian Zheng

  2. School of Medicine, Nankai University, Tianjin, China

    Wei Zhang & Mengran Tian

  3. Salk Institute for Biological Studies, La Jolla, CA, 92037, USA

    Jianfeng Huang

  4. State Key Laboratory of Medicinal Chemical Biology and College of Life Sciences, Nankai University, Tianjin, China

    Yuyang Qian

  5. School of Pharmacy, Tianjin Medical University, Tianjin Key Laboratory on Technologies Enabling Development Clinical Therapeutics and Diagnostics (Theragnostic), Tianjin, China

    Nan Qin

  6. Key Laboratory of Immune Microenvironment and Disease (Ministry of Education), The Province and Ministry Co-sponsored Collaborative Innovation Center for Medical Epigenetics, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Tianjin Institute of Urology, The Second Hospital of Tianjin Medical University, Tianjin Medical University, Tianjin, China

    Yupeng Chen

  7. Tianjin Union Medical Center, Tianjin, China

    Ming Gao

Authors
  1. Xianhui Ruan
    View author publications

    Search author on:PubMed Google Scholar

  2. Wei Zhang
    View author publications

    Search author on:PubMed Google Scholar

  3. Xiukun Hou
    View author publications

    Search author on:PubMed Google Scholar

  4. Guiming Fu
    View author publications

    Search author on:PubMed Google Scholar

  5. Weike Ma
    View author publications

    Search author on:PubMed Google Scholar

  6. Jianfeng Huang
    View author publications

    Search author on:PubMed Google Scholar

  7. Yuyang Qian
    View author publications

    Search author on:PubMed Google Scholar

  8. Mengran Tian
    View author publications

    Search author on:PubMed Google Scholar

  9. Nan Qin
    View author publications

    Search author on:PubMed Google Scholar

  10. Yupeng Chen
    View author publications

    Search author on:PubMed Google Scholar

  11. Ming Gao
    View author publications

    Search author on:PubMed Google Scholar

  12. Dapeng Li
    View author publications

    Search author on:PubMed Google Scholar

  13. Xiangqian Zheng
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Xiangqian Zheng: writing—review & editing, writing—original draft, validation, software, resources, methodology, investigation, funding acquisition. Xianhui Ruan: writing—review & editing, validation, software, resources, methodology, investigation, data curation, conceptualisation, funding acquisition. Wei Zhang: writing—review & editing, resources, methodology, investigation, conceptualisation. Xiukun Hou: writing—original draft, validation, software, investigation, formal analysis, data curation. Guiming Fu: resources. Weike Ma: supervision, software, resources, investigation. Jianfeng Huang: writing—original draft, supervision, resources, methodology, investigation. Yuyang Qian: software, project administration, investigation, data curation. Mengran Tian: software, methodology, formal analysis, data curation. Nan Qin: validation, software, investigation. Yupeng Chen: writing—review & editing. Ming Gao: writing—review & editing, supervision, project administration, funding acquisition, conceptualisation. Dapeng Li: writing—review & editing, validation, supervision, project administration, funding acquisition.

Corresponding authors

Correspondence to Dapeng Li or Xiangqian Zheng.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

The present study was approved by the Ethics Committee of the Tianjin Medical University Cancer Institute and Hospital (EK2021149), and was performed according to the Declaration of Helsinki.

Consent for publication

All co-authors have read and approved the final version of the manuscript and its submission to this journal.

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

Ruan, X., Zhang, W., Hou, X. et al. Enhancer hijacking drives FAM20C expression to promote papillary thyroid cancer progression. Cancer Gene Ther 32, 854–869 (2025). https://doi.org/10.1038/s41417-025-00930-8

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Version of record:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41417-025-00930-8

Search

Advanced search

Quick links