[go: up one dir, main page]
More Web Proxy on the site http://driver.im/
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.

  • Brief Communication
  • Published:

NKX2-1 controls lung cancer progression by inducing DUSP6 to dampen ERK activity

Oncogene volume 41, pages 293–300 (2022)Cite this article

Subjects

Abstract

The RAS→RAF→MEK→ERK pathway is hyperactivated in the majority of human lung adenocarcinoma (LUAD). However, the initial activating mutations induce homeostatic feedback mechanisms that limit ERK activity. How ERK activation reaches the tumor-promoting levels that overcome the feedback and drive malignant progression is unclear. We show here that the lung lineage transcription factor NKX2-1 suppresses ERK activity. In human tissue samples and cell lines, xenografts, and genetic mouse models, NKX2-1 induces the ERK phosphatase DUSP6, which inactivates ERK. In tumor cells from late-stage LUAD with silenced NKX2-1, re-introduction of NKX2-1 induces DUSP6 and inhibits tumor growth and metastasis. We show that DUSP6 is necessary for NKX2-1-mediated inhibition of tumor progression in vivo and that DUSP6 expression is sufficient to inhibit RAS-driven LUAD. Our results indicate that NKX2-1 silencing, and thereby DUSP6 downregulation, is a mechanism by which early LUAD can unleash ERK hyperactivation for tumor progression.

Access through your institution
Buy or subscribe

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Fig. 1: NKX2-1 transcriptionally induces DUSP6.
Fig. 2: NKX2-1 inhibits cell proliferation, migration and invasion, and tumor growth, dissemination, and ERK activity.
Fig. 3: NKX2-1 requires DUSP6 to slow cell proliferation and migration.
Fig. 4: NKX2-1 controls tumor progression through DUSP6.

Similar content being viewed by others

References

  1. Cancer Genome Atlas Research N. Comprehensive molecular profiling of lung adenocarcinoma. Nature. 2014;511:543–50.

    Article  Google Scholar 

  2. Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, et al. Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 2008;455:1069–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dankort D, Filenova E, Collado M, Serrano M, Jones K, McMahon M. A new mouse model to explore the initiation, progression, and therapy of BRAFV600E-induced lung tumors. Genes Dev. 2007;21:379–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Blasco RB, Francoz S, Santamaria D, Canamero M, Dubus P, Charron J, et al. c-Raf, but not B-Raf, is essential for development of K-Ras oncogene-driven non-small cell lung carcinoma. Cancer cell. 2011;19:652–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Trejo CL, Juan J, Vicent S, Sweet-Cordero A, McMahon M. MEK1/2 inhibition elicits regression of autochthonous lung tumors induced by KRASG12D or BRAFV600E. Cancer Res. 2012;72:3048–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Jackson EL, Olive KP, Tuveson DA, Bronson R, Crowley D, Brown M, et al. The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 2005;65:10280–8.

    Article  CAS  PubMed  Google Scholar 

  7. Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, et al. Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature. 2001;410:1111–6.

    Article  CAS  PubMed  Google Scholar 

  8. Noguchi M. Stepwise progression of pulmonary adenocarcinoma-clinical and molecular implications. Cancer metastasis Rev. 2010;29:15–21.

    Article  PubMed  Google Scholar 

  9. Vicent S, Lopez-Picazo JM, Toledo G, Lozano MD, Torre W, Garcia-Corchon C, et al. ERK1/2 is activated in non-small-cell lung cancer and associated with advanced tumours. Br J Cancer. 2004;90:1047–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Feldser DM, Kostova KK, Winslow MM, Taylor SE, Cashman C, Whittaker CA, et al. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature. 2010;468:572–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Gilbert-Ross M, Konen J, Koo J, Shupe J, Robinson BS. Wiles WGt et al. Targeting adhesion signaling in KRAS, LKB1 mutant lung adenocarcinoma. JCI Insight. 2017;2:e90487.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Junttila MR, Karnezis AN, Garcia D, Madriles F, Kortlever RM, Rostker F, et al. Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature. 2010;468:567–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Heidorn SJ, Milagre C, Whittaker S, Nourry A, Niculescu-Duvas I, Dhomen N, et al. Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. Cell. 2010;140:209–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nieto P, Ambrogio C, Esteban-Burgos L, Gomez-Lopez G, Blasco MT, Yao Z, et al. A Braf kinase-inactive mutant induces lung adenocarcinoma. Nature. 2017;548:239–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cicchini M, Buza EL, Sagal KM, Gudiel AA, Durham AC, Feldser DM. Context-Dependent Effects of Amplified MAPK Signaling during Lung Adenocarcinoma Initiation and Progression. Cell Rep. 2017;18:1958–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Russell PA, Wainer Z, Wright GM, Daniels M, Conron M, Williams RA. Does lung adenocarcinoma subtype predict patient survival?: A clinicopathologic study based on the new International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society international multidisciplinary lung adenocarcinoma classification. J Thorac Oncol. 2011;6:1496–504.

    Article  PubMed  Google Scholar 

  17. Yoshizawa A, Motoi N, Riely GJ, Sima CS, Gerald WL, Kris MG, et al. Impact of proposed IASLC/ATS/ERS classification of lung adenocarcinoma: prognostic subgroups and implications for further revision of staging based on analysis of 514 stage I cases. Mod Pathol. 2011;24:653–64.

    Article  CAS  PubMed  Google Scholar 

  18. Snyder EL, Watanabe H, Magendantz M, Hoersch S, Chen TA, Wang DG, et al. Nkx2-1 represses a latent gastric differentiation program in lung adenocarcinoma. Mol cell. 2013;50:185–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Winslow MM, Dayton TL, Verhaak RG, Kim-Kiselak C, Snyder EL, Feldser DM, et al. Suppression of lung adenocarcinoma progression by Nkx2-1. Nature. 2011;473:101–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Marjanovic ND, Hofree M, Chan JE, Canner D, Wu K, Trakala M, et al. Emergence of a high-plasticity cell state during lung cancer evolution. Cancer cell. 2020;38:229–46 e213.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Takeuchi T, Tomida S, Yatabe Y, Kosaka T, Osada H, Yanagisawa K, et al. Expression profile-defined classification of lung adenocarcinoma shows close relationship with underlying major genetic changes and clinicopathologic behaviors. J Clin Oncol. 2006;24:1679–88.

    Article  CAS  PubMed  Google Scholar 

  22. Yatabe Y, Kosaka T, Takahashi T, Mitsudomi T. EGFR mutation is specific for terminal respiratory unit type adenocarcinoma. Am J Surg Pathol. 2005;29:633–9.

    Article  PubMed  Google Scholar 

  23. Maeda Y, Tsuchiya T, Hao H, Tompkins DH, Xu Y, Mucenski ML, et al. Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung. J Clin Investig. 2012;122:4388–4400.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Nunes-Xavier C, Roma-Mateo C, Rios P, Tarrega C, Cejudo-Marin R, Tabernero L, et al. Dual-specificity MAP kinase phosphatases as targets of cancer treatment. Anti-cancer agents medicinal Chem. 2011;11:109–32.

    Article  CAS  Google Scholar 

  25. Kidger AM, Keyse SM. The regulation of oncogenic Ras/ERK signalling by dual-specificity mitogen activated protein kinase phosphatases (MKPs). Semin Cell Dev Biol. 2016;50:125–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Muda M, Theodosiou A, Rodrigues N, Boschert U, Camps M, Gillieron C, et al. The dual specificity phosphatases M3/6 and MKP-3 are highly selective for inactivation of distinct mitogen-activated protein kinases. J Biol Chem. 1996;271:27205–8.

    Article  CAS  PubMed  Google Scholar 

  27. Unni AM, Harbourne B, Oh MH, Wild S, Ferrarone JR, Lockwood WW, et al. Hyperactivation of ERK by multiple mechanisms is toxic to RTK-RAS mutation-driven lung adenocarcinoma cells. Elife. 2018;7:e33718.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Chen HY, Yu SL, Chen CH, Chang GC, Chen CY, Yuan A, et al. A five-gene signature and clinical outcome in non-small-cell lung cancer. N. Engl J Med. 2007;356:11–20.

    Article  CAS  PubMed  Google Scholar 

  29. Watanabe H, Francis JM, Woo MS, Etemad B, Lin W, Fries DF, et al. Integrated cistromic and expression analysis of amplified NKX2-1 in lung adenocarcinoma identifies LMO3 as a functional transcriptional target. Genes Dev (Res Support, N. I H, Extramural). 2013;27:197–210.

    CAS  Google Scholar 

  30. Okudela K, Yazawa T, Woo T, Sakaeda M, Ishii J, Mitsui H, et al. Down-regulation of DUSP6 expression in lung cancer: its mechanism and potential role in carcinogenesis. Am J Pathol. 2009;175:867–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Ding W, Bellusci S, Shi W, Warburton D. Functional analysis of the human Sprouty2 gene promoter. Gene. 2003;322:175–85.

    Article  CAS  PubMed  Google Scholar 

  32. Ekerot M, Stavridis MP, Delavaine L, Mitchell MP, Staples C, Owens DM, et al. Negative-feedback regulation of FGF signalling by DUSP6/MKP-3 is driven by ERK1/2 and mediated by Ets factor binding to a conserved site within the DUSP6/MKP-3 gene promoter. Biochem J. 2008;412:287–98.

    Article  CAS  PubMed  Google Scholar 

  33. Camolotto SA, Pattabiraman S, Mosbruger TL, Jones A, Belova VK, Orstad G, et al. FoxA1 and FoxA2 drive gastric differentiation and suppress squamous identity in NKX2-1-negative lung cancer. Elife. 2018;7:e38579.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Li CM, Gocheva V, Oudin MJ, Bhutkar A, Wang SY, Date SR, et al. Foxa2 and Cdx2 cooperate with Nkx2-1 to inhibit lung adenocarcinoma metastasis. Genes Dev. 2015;29:1850–62.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Minoo P, Hu L, Xing Y, Zhu NL, Chen H, Li M, et al. Physical and functional interactions between homeodomain NKX2.1 and winged helix/forkhead FOXA1 in lung epithelial cells. Mol Cell Biol. 2007;27:2155–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gillies TE, Pargett M, Silva JM, Teragawa CK, McCormick F, Albeck JG. Oncogenic mutant RAS signaling activity is rescaled by the ERK/MAPK pathway. Mol Syst Biol. 2020;10:e9518.

    Google Scholar 

  37. Zewdu R, Mehrabad EM, Ingram K, Fang P, Gillis KL, Camolotto SA, et al. An NKX2-1/ERK/WNT feedback loop modulates gastric identity and response to targeted therapy in lung adenocarcinoma. Elife. 2021;10:e66788.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Premsrirut PK, Dow LE, Kim SY, Camiolo M, Malone CD, Miething C, et al. A rapid and scalable system for studying gene function in mice using conditional RNA interference. Cell. 2011;145:145–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sutherland KD, Song JY, Kwon MC, Proost N, Zevenhoven J, Berns A. Multiple cells-of-origin of mutant K-Ras-induced mouse lung adenocarcinoma. Proc Natl Acad Sci USA. 2014;111:4952–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Xu X, Rock JR, Lu Y, Futtner C, Schwab B, Guinney J, et al. Evidence for type II cells as cells of origin of K-Ras-induced distal lung adenocarcinoma. Proc Natl Acad Sci USA. 2012;109:4910–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kong XJ, Kuilman T, Shahrabi A, Oshuizen JB, Kemper K, Song JY, et al. Cancer drug addiction is relayed by an ERK2-dependent phenotype switch. Nature. 2017;550:270-+.

    Article  PubMed  PubMed Central  Google Scholar 

  42. Hrustanovic G, Olivas V, Pazarentzos E, Tulpule A, Asthana S, Blakely CM, et al. RAS-MAPK dependence underlies a rational polytherapy strategy in EML4-ALK-positive lung cancer. Nat Med. 2015;21:1038–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Davies AE, Pargett M, Siebert S, Gillies TE, Choi Y, Tobin SJ, et al. Systems-level properties of EGFR-RAS-ERK signaling amplify local signals to generate dynamic gene expression heterogeneity. Cell Syst. 2020;11:161–75 e165.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Thanks to Dr. Stephen Keyse for the gift of the DUSP6 promoter constructs and Dr. Doug Mackay for H2B-mCherry-N2. Thanks to Keith Carney for the development of software for automated cell migration tracking. Flow cytometry was supported by the University of Utah Flow Cytometry Facility and funding from 5P30CA042014-24 and 1S10RR026802-01. Thanks to the University of Utah Cell Imaging Core and the Huntsman Cancer Institute Preclinical Research Resource. M.C.M was supported by K01CA168850, R21CA215891, an American Lung Association Research Grant, American Cancer Society RSG CSM130435, and V Scholar Award. E.L.S. was supported by a Career Award for Medical Scientists from the Burroughs Wellcome Fund, a V Scholar Award, and R01CA212415 and R01CA240317.

Author information

Author notes

  1. These authors contributed equally: Kelley Ingram, Shiela C. Samson.

Authors and Affiliations

  1. Department of Oncological Sciences, University of Utah, Salt Lake City, UT, 84112, USA

    Kelley Ingram, Shiela C. Samson, Eric L. Snyder & Michelle C. Mendoza

  2. Huntsman Cancer Institute, Salt Lake City, UT, 84112, USA

    Kelley Ingram, Shiela C. Samson, Rediet Zewdu, Rebecca G. Zitnay, Eric L. Snyder & Michelle C. Mendoza

  3. Department of Pathology, University of Utah, Salt Lake City, UT, 84112, USA

    Rediet Zewdu & Eric L. Snyder

  4. Department of Biomedical Engineering, University of Utah, Salt Lake City, UT, 84112, USA

    Rebecca G. Zitnay & Michelle C. Mendoza

Authors
  1. Kelley Ingram
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shiela C. Samson
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rediet Zewdu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rebecca G. Zitnay
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eric L. Snyder
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michelle C. Mendoza
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ELS and MCM conceptualized the study. KI, SCS, RGZ, RZ, ELS, and MCM carried out the investigation and extraction of the results. SCS, ELS, and MCM designed the methods and carried out formal analysis and interpretation of the results. MCM managed data curation, project administration, acquisition of study funding, and writing the original manuscript draft. All co-authors were involved in review and editing of the manuscript.

Corresponding author

Correspondence to Michelle C. Mendoza.

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

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ingram, K., Samson, S.C., Zewdu, R. et al. NKX2-1 controls lung cancer progression by inducing DUSP6 to dampen ERK activity. Oncogene 41, 293–300 (2022). https://doi.org/10.1038/s41388-021-02076-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-021-02076-x

This article is cited by

Search

Advanced search

Quick links