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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Lin, C-C; Yang, W-H; Lin, Y-T; Tang, X; Chen, P-H; Ding, C-KC; Qu, DC; Alvarez, JV; Chi, J-T

Published Date

  • March 2021

Published In

Volume / Issue

  • 40 / 11

Start / End Page

  • 2018 - 2034

PubMed ID

  • 33603168

Pubmed Central ID

  • PMC7988308

Electronic International Standard Serial Number (EISSN)

  • 1476-5594

Digital Object Identifier (DOI)

  • 10.1038/s41388-021-01676-x

Language

  • eng

Conference Location

  • England