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

Hongyu Wang1, Shipeng Dai1, Yuchen Xie1

  • 1Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Liver Transplantation, Chinese Academy of Medical Sciences, NHC Key laboratory of Hepatobiliary cancers, Nanjing, 210036, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|December 12, 2025
PubMed

Insights

Researchers identified RNF32 as a key gene in colorectal cancer liver metastasis (CRLM). RNF32 promotes tumor growth and metastasis by influencing the Wnt pathway and immune cells, with indole-3-acetic acid (IAA) showing therapeutic potential.

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.
Keywords:
RNF32SPP1+ macrophagecolorectal cancer liver metastasisepithelial‐mesenchymal transitionindole‐3‐acetic acid

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