RIPK3 upregulation confers robust proliferation and collateral cystine-dependence on breast cancer recurrence.

Journal Article (Journal Article)

The molecular and genetic basis of tumor recurrence is complex and poorly understood. RIPK3 is a key effector in programmed necrotic cell death and, therefore, its expression is frequently suppressed in primary tumors. In a transcriptome profiling between primary and recurrent breast tumor cells from a murine model of breast cancer recurrence, we found that RIPK3, while absent in primary tumor cells, is dramatically reexpressed in recurrent breast tumor cells by an epigenetic mechanism. Unexpectedly, we found that RIPK3 knockdown in recurrent tumor cells reduced clonogenic growth, causing cytokinesis failure, p53 stabilization, and repressed the activities of YAP/TAZ. These data uncover a surprising role of the pro-necroptotic RIPK3 kinase in enabling productive cell cycle during tumor recurrence. Remarkably, high RIPK3 expression also rendered recurrent tumor cells exquisitely dependent on extracellular cystine and undergo necroptosis upon cystine deprivation. The induction of RIPK3 in recurrent tumors unravels an unexpected mechanism that paradoxically confers on tumors both growth advantage and necrotic vulnerability, providing potential strategies to eradicate recurrent tumors.

Full Text

Duke Authors

Cited Authors

  • Lin, C-C; Mabe, NW; Lin, Y-T; Yang, W-H; Tang, X; Hong, L; Sun, T; Force, J; Marks, JR; Yao, T-P; Alvarez, JV; Chi, J-T

Published Date

  • July 2020

Published In

Volume / Issue

  • 27 / 7

Start / End Page

  • 2234 - 2247

PubMed ID

  • 31988496

Pubmed Central ID

  • PMC7308288

Electronic International Standard Serial Number (EISSN)

  • 1476-5403

Digital Object Identifier (DOI)

  • 10.1038/s41418-020-0499-y


  • eng

Conference Location

  • England