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

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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.

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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.

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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.

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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.

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Authors and Affiliations

  1. Cell Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Alexander M. Minikes, Yu Song, Yan Feng & Xuejun Jiang

  2. Department of Oncology, Affiliated Zhangjiagang Hospital, Soochow University, Suzhou, China

    Yu Song

  3. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA

    Changhwan Yoon & Sam S. Yoon

  4. Department of Surgery, Columbia University Irving Medical Center, New York, NY, 10032, USA

    Changhwan Yoon & Sam S. Yoon

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  1. Alexander M. Minikes
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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.

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Correspondence to Yu Song or Xuejun Jiang.

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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.

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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

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