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DDR2 upregulation confers ferroptosis susceptibility of recurrent breast tumors through the Hippo pathway

Abstract

Recurrent breast cancer presents significant challenges with aggressive phenotypes and treatment resistance. Therefore, novel therapeutics are urgently needed. Here, we report that murine recurrent breast tumor cells, when compared with primary tumor cells, are highly sensitive to ferroptosis. Discoidin Domain Receptor Tyrosine Kinase 2 (DDR2), the receptor for collagen I, is highly expressed in ferroptosis-sensitive recurrent tumor cells and human mesenchymal breast cancer cells. EMT regulators, TWIST and SNAIL, significantly induce DDR2 expression and sensitize ferroptosis in a DDR2-dependent manner. Erastin treatment induces DDR2 upregulation and phosphorylation, independent of collagen I. Furthermore, DDR2 knockdown in recurrent tumor cells reduces clonogenic proliferation. Importantly, both the ferroptosis protection and reduced clonogenic growth may be compatible with the compromised YAP/TAZ upon DDR2 inhibition. Collectively, these findings identify the important role of EMT-driven DDR2 upregulation in recurrent tumors in maintaining growth advantage but activating YAP/TAZ-mediated ferroptosis susceptibility, providing potential strategies to eradicate recurrent breast cancer cells with mesenchymal features.

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Fig. 1: Recurrent tumor cells are sensitive to ferroptosis and show high DDR2 expression.
Fig. 2: Genetic and chemical inhibition of DDR2 rescued ferroptosis in recurrent tumor cells.
Fig. 3: EMT regulators upregulate DDR2 expression.
Fig. 4: EMT-mediated DDR2 upregulation determines its sensitivity to ferroptosis.
Fig. 5: DDR2 regulates cell proliferation and YAP/TAZ activity.
Fig. 6: DDR2 phosphorylation sensitizes YAP/TAZ-mediated ferroptosis through Src activity.

Data availability

All data and reagents supporting the findings of this study are available from the authors upon reasonable request.

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Acknowledgements

We are grateful for technical support from the members of the Chi lab. We also appreciate the generosity of Dr. Everardo Macias for allowing access to the Incucyte S3. We acknowledge the financial support in part by DOD grants (W81XWH-17-1-0143, W81XWH-15-1-0486, W81XWH-19-1-0842, W81XWH-20-1-0907), and NIH grants (R01GM124062, 1R01NS111588-01A1, 1R21-AI149205).

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CCL and JTC conceived the experiments and wrote the paper. CCL performed the majority of the experiments. JTC supervised the work. WHY, YTL, XT, PHC, CKD, DCQ, and JA collaborated in the discussion and experiments. JTC and JA provided critical feedback.

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Correspondence to Jen-Tsan Chi.

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Lin, CC., Yang, WH., Lin, YT. et al. DDR2 upregulation confers ferroptosis susceptibility of recurrent breast tumors through the Hippo pathway. Oncogene 40, 2018–2034 (2021). https://doi.org/10.1038/s41388-021-01676-x

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