Targeting BRD3 eradicates nuclear TYRO3-induced colorectal cancer metastasis

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metastasis Research

Background:

• Metastasis is the primary cause of cancer mortality, particularly in colorectal cancer (CRC).
• The molecular mechanisms driving metastatic progression in CRC are not fully understood.
• Nuclear TYRO3 receptor tyrosine kinase has been identified as a potential prognostic marker in CRC.

Purpose of the Study:

• To elucidate the role of nuclear TYRO3 in colorectal cancer metastasis.
• To identify downstream targets and signaling pathways regulated by nuclear TYRO3.
• To evaluate the therapeutic potential of targeting the TYRO3 signaling axis in CRC.

Main Methods:

• Proteomic analysis to identify substrates of nuclear TYRO3.
• Chromatin immunoprecipitation-sequencing (ChIP-seq) to determine BRD3-regulated genes.
• Inhibition studies using selective inhibitors of MMP-2 and BRD3 in organoid and mouse models.

Main Results:

• Nuclear TYRO3 promotes CRC metastasis through kinase activity and MMP-2 cleavage, independent of ligand binding.
• Bromodomain-containing protein 3 (BRD3) was identified as a substrate of TYRO3; TYRO3-phosphorylated BRD3 regulates genes involved in anti-apoptosis and epithelial-mesenchymal transition.
• Inhibition of MMP-2 or BRD3 abrogated nuclear TYRO3-induced drug resistance and metastasis in preclinical models.

Conclusions:

• The MMP-2/TYRO3/BRD3 signaling axis is a critical driver of colorectal cancer metastasis and drug resistance.
• Targeting this axis represents a promising therapeutic strategy to reduce CRC malignancy.
• Nuclear TYRO3 is a significant predictor of poor survival in CRC patients.