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:

E-cadherin is a biomarker for ferroptosis sensitivity in diffuse gastric cancer

Abstract

Gastric cancer is the third most common cause of cancer-related death worldwide. Diffuse-type gastric cancer (DGC) is a particularly aggressive subtype that is both difficult to detect and treat. DGC is distinguished by weak cell–cell cohesion, most often due to loss of the cell adhesion protein E-cadherin, a common occurrence in highly invasive, metastatic cancer cells. In this study, we demonstrate that loss-of-function mutation of E-cadherin in DGC cells results in their increased sensitivity to the non-apoptotic, iron-dependent form of cell death, ferroptosis. Homophilic contacts between E-cadherin molecules on adjacent cells suppress ferroptosis through activation of the Hippo pathway. Furthermore, single nucleotide mutations observed in DGC patients that ablate the homophilic binding capacity of E-cadherin reverse the ability of E-cadherin to suppress ferroptosis in both cell culture and xenograft models. Importantly, although E-cadherin loss in cancer cells is considered an essential event for epithelial-mesenchymal transition and subsequent metastasis, we found that circulating DGC cells lacking E-cadherin expression possess lower metastatic ability, due to their increased susceptibility to ferroptosis. Together, this study suggests that E-cadherin is a biomarker predicting the sensitivity to ferroptosis of DGC cells, both in primary tumor tissue and in circulation, thus guiding the usage of future ferroptosis-inducing therapeutics for the treatment of DGC.

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

Access options

Buy this article

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

Fig. 1: Effect of cell density on ferroptosis of DGC cells.
Fig. 2: E-cadherin expression dictates cell density-regulated ferroptosis in DGC cells.
Fig. 3: Effect of patient-derived point mutations of E-cadherin on ferroptosis.
Fig. 4: Patient-derived point mutations alter various cellular functions of E-cadherin.
Fig. 5: NF2-Hippo-YAP pathway mediates the ferroptosis-regulatory function of E-cadherin in DGC cells.
Fig. 6: E-cadherin mutation sensitizes DGC cells to ferroptosis induction in vivo and mitigates lung metastasis of circulating DGC cells.

Similar content being viewed by others

Data availability

All raw data values and Western blots are available as Supplementary Data. All other relevant data are available upon request from the authors.

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. Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol. 2006;12:354–62.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Ansari S, Gantuya B, Tuan VP, Yamaoka Y. Diffuse gastric cancer: a summary of analogous contributing factors for its molecular pathogenicity. Int J Mol Sci. 2018;19:2424.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Liu X, Chu K-M. E-cadherin and gastric cancer: cause, consequence, and applications. Biomed Res Int. 2014;2014:637308.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kaurah P, MacMillan A, Boyd N, Senz J, De Luca A, Chun N, et al. Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. JAMA. 2007;297:2360–72.

    Article  CAS  PubMed  Google Scholar 

  6. Till JE, Yoon C, Kim B-J, Roby K, Addai P, Jonokuchi E, et al. Oncogenic KRAS and p53 loss drive gastric tumorigenesis in mice that can be attenuated by E-cadherin expression. Cancer Res. 2017;77:5349–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lewis FR, Mellinger JD, Hayashi A, Lorelli D, Monaghan KG, Carneiro F, et al. Prophylactic total gastrectomy for familial gastric cancer. Surgery. 2001;130:612–7. discussion 617–9.

    Article  CAS  PubMed  Google Scholar 

  8. Shenoy S. CDH1 (E-cadherin) mutation and gastric cancer: genetics, molecular mechanisms and guidelines for management. Cancer Manag Res. 2019;11:10477–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Pandalai PK, Lauwers GY, Chung DC, Patel D, Yoon SS. Prophylactic total gastrectomy for individuals with germline CDH1 mutation. Surgery. 2011;149:347–55.

    Article  PubMed  Google Scholar 

  10. Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, Polkowski WP. Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Manag Res. 2018;10:239–48.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. van Roy F, Berx G. The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci. 2008;65:3756–88.

    Article  CAS  PubMed  Google Scholar 

  12. Perez-Moreno M, Fuchs E. Catenins: keeping cells from getting their signals crossed. Dev Cell. 2006;11:601–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Koch AW, Manzur KL, Shan W. Structure-based models of cadherin-mediated cell adhesion: the evolution continues. Cell Mol Life Sci. 2004;61:1884–95.

    Article  CAS  PubMed  Google Scholar 

  14. Shapiro L, Fannon AM, Kwong PD, Thompson A, Lehmann MS, Grübel G, et al. Structural basis of cell-cell adhesion by cadherins. Nature. 1995;374:327–37.

    Article  CAS  PubMed  Google Scholar 

  15. Parisini E, Higgins JM, Liu JH, Brenner MB, Wang JH. The crystal structure of human E-cadherin domains 1 and 2, and comparison with other cadherins in the context of adhesion mechanism. J Mol Biol. 2007;373:401–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Boggon TJ, Murray J, Chappuis-Flament S, Wong E, Gumbiner BM, Shapiro L. C-cadherin ectodomain structure and implications for cell adhesion mechanisms. Science. 2002;296:1308–13.

    Article  CAS  PubMed  Google Scholar 

  17. Brieher WM, Yap AS, Gumbiner BM. Lateral dimerization is required for the homophilic binding activity of C-cadherin. J Cell Biol. 1996;135:487–96.

    Article  CAS  PubMed  Google Scholar 

  18. Wu J, Minikes AM, Gao M, Bian H, Li Y, Stockwell BR, et al. Intercellular interaction dictates cancer cell ferroptosis via NF2-YAP signalling. Nature. 2019;572:402–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Kim NG, Koh E, Chen X, Gumbiner BM. E-cadherin mediates contact inhibition of proliferation through Hippo signaling-pathway components. Proc Natl Acad Sci USA. 2011;108:11930–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Meng Z, Moroishi T, Guan KL. Mechanisms of Hippo pathway regulation. Genes Dev. 2016;30:1–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Kim TY, Jong H-S, Jung Y, Kim T-Y, Kang GH, Bang Y-J. DNA hypermethylation in gastric cancer. Aliment Pharmacol Ther. 2004;20:131–42.

    Article  CAS  PubMed  Google Scholar 

  22. Handschuh G, Candidus S, Luber B, Reich U, Schott C, Oswald S, et al. Tumour-associated E-cadherin mutations alter cellular morphology, decrease cellular adhesion and increase cellular motility. Oncogene. 1999;18:4301–12.

    Article  CAS  PubMed  Google Scholar 

  23. Figueiredo J, Ferreira RM, Xu H, Gonçalves M, Barros-Carvalho A, Cravo J, et al. Integrin β1 orchestrates the abnormal cell-matrix attachment and invasive behaviour of E-cadherin dysfunctional cells. Gastric Cancer. 2022;25:124–37.

    Article  CAS  PubMed  Google Scholar 

  24. Yang WH, Ding CC, Sun T, Rupprecht G, Lin CC, Hsu D, et al. The Hippo pathway effector TAZ regulates ferroptosis in renal cell carcinoma. Cell Rep. 2019;28:2501.e2504.

    Article  CAS  PubMed  Google Scholar 

  25. Gao M, Monian P, Quadri N, Ramasamy R, Jiang X. Glutaminolysis and transferrin regulate ferroptosis. Mol Cell. 2015;59:298–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Kagan VE, Mao G, Qu F, Angeli JP, Doll S, Croix CS, et al. Oxidized arachidonic and adrenic PEs navigate cells to ferroptosis. Nat Chem Biol. 2017;13:81–90.

    Article  CAS  PubMed  Google Scholar 

  27. Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, et al. ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition. Nat Chem Biol. 2017;13:91–8.

    Article  CAS  PubMed  Google Scholar 

  28. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Qin Y, Pei Z, Feng Z, Lin P, Wang S, Li Y, et al. Oncogenic activation of YAP signaling sensitizes ferroptosis of hepatocellular carcinoma via ALOXE3-mediated lipid peroxidation accumulation. Front Cell Dev Biol. 2021;9:751593.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Padmanaban V, Krol I, Suhail Y, Szczerba BM, Aceto N, Bader JS, et al. E-cadherin is required for metastasis in multiple models of breast cancer. Nature. 2019;573:439–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Janjigian YY, Shitara K, Moehler M, Garrido M, Salman P, Shen L, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. Lancet. 2021;398:27–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Yuan H, Li X, Zhang X, Kang R, Tang D. Identification of ACSL4 as a biomarker and contributor of ferroptosis. Biochem Biophys Res Commun. 2016;478:1338–43.

    Article  CAS  PubMed  Google Scholar 

  33. Feng H, Schorpp K, Jin J, Yozwiak CE, Hoffstrom BG, Decker AM, et al. Transferrin receptor is a specific ferroptosis marker. Cell Rep. 2020;30:3411–23.e3417.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Hangauer MJ, Viswanathan VS, Ryan MJ, Bole D, Eaton JK, Matov A, et al. Drug-tolerant persister cancer cells are vulnerable to GPX4 inhibition. Nature. 2017;551:247–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Viswanathan VS, Ryan MJ, Dhruv HD, Gill S, Eichhoff OM, Seashore-Ludlow B, et al. Dependency of a therapy-resistant state of cancer cells on a lipid peroxidase pathway. Nature. 2017;547:453–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Yamaguchi H, Taouk GM. A potential role of YAP/TAZ in the interplay between metastasis and metabolic alterations. Front Oncol (Rev). 2020;10:928.

    Article  Google Scholar 

  37. Heerboth S, Housman G, Leary M, Longacre M, Byler S, Lapinska K, et al. EMT and tumor metastasis. Clin Transl Med. 2015;4:6.

  38. Ubellacker JM, Tasdogan A, Ramesh V, Shen B, Mitchell EC, Martin-Sandoval MS, et al. Lymph protects metastasizing melanoma cells from ferroptosis. Nature. 2020;585:113–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Padmanaban V, Krol I, Suhail Y, Szczerba BM, Aceto N, Bader JS, et al. E-cadherin is required for metastasis in multiple models of breast cancer. Nature. 2019;573:439–44.

  40. Forcina GC, Conlon M, Wells A, Cao JY, Dixon SJ. Systematic quantification of population cell death kinetics in mammalian cells. Cell Syst. 2017;4:600–10.e606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors thank members of the Jiang lab for critical reading and suggestions. This work is supported by NIH F31CA247112 (to AMM), NIH R01CA204232 and NIH R01CA258622 (to XJ), and NCI cancer center core grant P30 CA008748 to MSKCC.

Author information

Authors and Affiliations

Authors

Contributions

AMM, YS, and XJ conceived and designed the study. AMM performed most of the experiments, with contributions from YS and CY. CY and SSY contributed materials and advice. AMM, YS, and XJ performed data analysis and wrote the manuscript. All authors contributed to the writing and editing of the manuscript.

Corresponding authors

Correspondence to Yu Song or Xuejun Jiang.

Ethics declarations

Competing interests

XJ and AMM are inventors of patents relevant to ferroptosis and autophagy. XJ is a consultant and equity holder of Exarta Therapeutics and Lime Therapeutics. The rest of 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

Minikes, A.M., Song, Y., Feng, Y. et al. E-cadherin is a biomarker for ferroptosis sensitivity in diffuse gastric cancer. Oncogene 42, 848–857 (2023). https://doi.org/10.1038/s41388-023-02599-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41388-023-02599-5

This article is cited by

Search

Quick links