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

Area of Science:

• Oncology
• Molecular Biology
• Cell Death Research

Background:

• Tumor recurrence mechanisms remain poorly understood.
• RIPK3 (receptor-interacting protein kinase 3), a programmed necrosis effector, is typically suppressed in primary tumors.

Purpose of the Study:

• To investigate the role of RIPK3 in breast cancer recurrence.
• To elucidate the molecular mechanisms by which RIPK3 influences tumor cell behavior during recurrence.

Main Methods:

• Transcriptome profiling of primary and recurrent murine breast tumor cells.
• RIPK3 knockdown experiments in recurrent tumor cells.
• Analysis of cell cycle, p53, YAP/TAZ activity, and cystine dependency.

Main Results:

• RIPK3 is epigenetically reexpressed in recurrent breast tumor cells.
• RIPK3 knockdown impairs clonogenic growth, causes cytokinesis failure, and stabilizes p53.
• RIPK3 promotes cell cycle progression and YAP/TAZ activity in recurrent tumors.
• High RIPK3 expression induces dependency on extracellular cystine, leading to necroptosis upon deprivation.

Conclusions:

• RIPK3 paradoxically supports tumor cell proliferation and survival during recurrence.
• RIPK3 reexpression creates a vulnerability to cystine deprivation, offering a potential therapeutic strategy.
• Targeting RIPK3-mediated pathways may provide novel approaches to eradicate recurrent breast cancers.