Abstract
Pancreatic ductal adenocarcinoma (PDAC) is an extremely aggressive malignancy prone to recurrence and metastasis. Studies show that tumor cells with increased invasive and metastatic potential are more likely to undergo ferroptosis. SMAD4 is a critical molecule in the transforming growth factor β (TGF-β) pathway, which affects the TGF-β-induced epithelial-mesenchymal transition (EMT) status. SMAD4 loss is observed in more than half of patients with PDAC. In this study, we investigated whether SMAD4-positive PDAC cells were prone to ferroptosis because of their high invasiveness. We showed that SMAD4 status almost determined the orientation of transforming growth factor β1 (TGF-β1)-induced EMT via the SMAD4-dependent canonical pathway in PDAC, which altered ferroptosis vulnerability. We identified glutathione peroxidase 4 (GPX4), which inhibited ferroptosis, as a SMAD4 down-regulated gene by RNA sequencing. We found that SMAD4 bound to the promoter of GPX4 and decreased GPX4 transcription in PDAC. Furthermore, TGF-β1-induced high invasiveness enhanced sensitivity of SMAD4-positive organoids and pancreas xenograft models to the ferroptosis inducer RAS-selective lethal 3 (RSL3). Moreover, SMAD4 enhanced the cytotoxic effect of gemcitabine combined with RSL3 in highly invasive PDAC cells. This study provides new ideas for the treatment of PDAC, especially SMAD4-positive PDAC.
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Acknowledgements
The work was supported by the National Natural Science Foundation of China (No. 82173281, 82141129, 82173282, 82172577 and 82172948); the Shanghai Municipal Science and Technology Commission (20ZR1471100); the Clinical and Scientific Innovation Project of Shanghai Hospital Development Center (SHDC12018109); the Scientific Innovation Project of Shanghai Education Committee (2019-01-07-00-07-E00057); the Shanghai Municipal Commission of Health and Family Planning (No. 2018YQ06); the Excellence Project of Shanghai Municipal Health Commission (20224Z0006); the Sailing Project of Science and Technology Commission of Shanghai Municipality (22YF1409000).
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Conceptualization, YQ, HDC, ZY and HFH; Methodology, HDC, YHH, GXF and ZL; Statistical analysis, HDC, BRL, SRJ and CJZ; Investigation, HDC, YQ, XWX and XJY; Writing, HDC and ZY; Supervision, XJY, XWX and YQ. All authors read and approved the final paper.
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This study was approved by the Institutional Research Ethics Committee of Fudan University Shanghai Cancer Centre (ethical code: 050432-4-1212B) and written informed consent was obtained from all patients.
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Chen, Hd., Ye, Z., Hu, Hf. et al. SMAD4 endows TGF-β1-induced highly invasive tumor cells with ferroptosis vulnerability in pancreatic cancer. Acta Pharmacol Sin 45, 844–856 (2024). https://doi.org/10.1038/s41401-023-01199-z
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DOI: https://doi.org/10.1038/s41401-023-01199-z