Colorectal Cancer Cell's Weapon: RNF32 Engages SPP1⁺ Macrophages to Foster Liver Metastasis, Targeted by...

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Colorectal cancer liver metastasis (CRLM) is a complex process with poorly understood molecular drivers.
• Identifying key genes and pathways is crucial for developing effective therapeutic strategies against CRLM.

Purpose of the Study:

• To identify novel molecular targets in CRLM.
• To elucidate the mechanisms by which these targets promote metastasis.
• To explore potential therapeutic interventions for CRLM.

Main Methods:

• Integration of The Cancer Genome Atlas (TCGA) data.
• Cox regression, Weighted Gene Co-expression Network Analysis (WGCNA), and single-cell RNA sequencing.
• In vitro and in vivo functional assays, mass cytometry, and virtual screening.

Main Results:

• RNF32 was identified as a key gene promoting tumor proliferation, invasion, and epithelial-mesenchymal transition (EMT).
• RNF32 stabilizes β-catenin, activates Wnt signaling, upregulates CCL2, and recruits SPP1+ macrophages to the metastatic niche.
• Indole-3-acetic acid (IAA) was identified as an RNF32 inhibitor that suppresses liver metastasis and reverses immunosuppression.

Conclusions:

• RNF32 is a critical driver of colorectal cancer liver metastasis through both tumor-intrinsic mechanisms (EMT) and modulation of the tumor immune microenvironment.
• The CCR2/FABP1/PPARG axis and SPP1+ macrophage recruitment are key components of the metastatic niche remodeling.
• Indole-3-acetic acid (IAA) represents a promising therapeutic agent for CRLM, targeting both tumor progression and immune evasion.