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DDR2 upregulation confers ferroptosis susceptibility of recurrent breast tumors through the Hippo pathway.
- Source :
-
Oncogene [Oncogene] 2021 Mar; Vol. 40 (11), pp. 2018-2034. Date of Electronic Publication: 2021 Feb 18. - Publication Year :
- 2021
-
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.
- Subjects :
- Animals
Breast Neoplasms pathology
Cell Cycle Proteins genetics
Cell Line, Tumor
Cell Movement genetics
Female
Fibroblasts metabolism
Fibroblasts pathology
Gene Expression Regulation, Neoplastic genetics
Hippo Signaling Pathway
Humans
Intracellular Signaling Peptides and Proteins genetics
Mice
Neoplasm Recurrence, Local pathology
Nuclear Proteins genetics
Phosphorylation
Piperazines pharmacology
Protein Serine-Threonine Kinases genetics
Signal Transduction genetics
Snail Family Transcription Factors genetics
Transcription Factors genetics
Transcriptional Coactivator with PDZ-Binding Motif Proteins
Twist-Related Protein 1 genetics
Breast Neoplasms genetics
Discoidin Domain Receptor 2 genetics
Ferroptosis genetics
Neoplasm Recurrence, Local genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1476-5594
- Volume :
- 40
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Oncogene
- Publication Type :
- Academic Journal
- Accession number :
- 33603168
- Full Text :
- https://doi.org/10.1038/s41388-021-01676-x