The RON receptor tyrosine kinase promotes metastasis by triggering MBD4-dependent DNA methylation reprogramming

Area of Science:

• Molecular Biology
• Cancer Research
• Epigenetics

Background:

• Metastasis is the primary cause of cancer-related mortality.
• The underlying genetic and epigenetic mechanisms driving metastasis remain largely unknown.
• Understanding these drivers is critical for developing effective cancer therapies.

Purpose of the Study:

• To identify and characterize the epigenetic reprogramming pathway essential for breast cancer metastasis.
• To elucidate the role of the RON receptor tyrosine kinase and MBD4 in this process.
• To investigate the clinical relevance of this epigenetic program in human breast cancers.

Main Methods:

• Investigated the activation of the RON receptor tyrosine kinase by macrophage stimulating protein (MSP).
• Utilized knockdown experiments to assess the function of MBD4 (thymine glycosylase).
• Analyzed DNA methylation patterns and gene expression changes.
• Examined patient-derived breast tumor grafts and human breast cancer samples.

Main Results:

• Activation of RON/MSP signaling promotes MBD4 expression, leading to aberrant DNA methylation.
• This aberrant methylation misregulates specific genes, driving breast cancer metastasis.
• MBD4 knockdown reversed methylation and inhibited metastasis; its catalytic activity was essential.
• The identified epigenetic program strongly correlates with poor clinical outcomes in breast cancer patients.

Conclusions:

• A novel epigenetic reprogramming pathway involving RON/MSP and MBD4 is critical for breast cancer metastasis.
• Targeting RON kinase activity effectively blocks metastasis in preclinical models.
• This pathway represents a potential therapeutic target for preventing cancer spread.