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Colorectal cancer liver metastasis remains a significant clinical hurdle for oncologists worldwide. Specifically, a recent study published in Experimental Hematology & Oncology identified the E3 ubiquitin ligase COP1 as a critical driver of this progression. This protein not only facilitates the spread of cancer to the liver but also contributes significantly to oxaliplatin resistance.
To understand these pathways, researchers utilized an organoid biobank derived from paired primary tumors and metastases. Consequently, they found that COP1 levels are significantly elevated in liver metastases compared to primary tumors. In addition, the study revealed that COP1 actively targets and degrades the protein LUZP1 through ubiquitination. Therefore, this degradation releases DAPK3 from its usual suppression. This sequence leads to enhanced MYL9 phosphorylation and triggers the epithelial-mesenchymal transition (EMT). Furthermore, it activates the JAK2-STAT3-CCND2 signaling axis. As a result, these activated pathways drive colorectal cancer liver metastasis and survival against standard chemotherapy.
High expression of COP1 correlates strongly with poor patient prognosis and a higher metastatic burden. Clinicians can now use COP1 profiling in patient-derived organoids (PDOs) to potentially predict responses to oxaliplatin-based regimens like FOLFOX. Thus, the COP1-LUZP1-MYL9 axis represents a promising therapeutic target for advanced colorectal cancer. Inhibiting this axis might reverse chemoresistance and limit the spread of metastatic cells. This research offers a new precision strategy for managing patients with aggressive metastatic disease.
COP1 promotes resistance by degrading LUZP1 and activating the JAK2-STAT3-CCND2 signaling pathway. This process allows cancer cells to survive the cytotoxic effects of oxaliplatin-based treatments.
MYL9 phosphorylation is enhanced when COP1 degrades LUZP1. This activation supports the epithelial-mesenchymal transition, which is a key step in the invasion and spread of colorectal cancer to the liver.
Yes, research suggests that COP1 levels in patient-derived organoids can help clinicians predict how a patient will respond to oxaliplatin-based chemotherapy, enabling more personalized treatment plans.
Disclaimer: This content is for informational and educational purposes only and does not constitute medical advice. Refer to the latest local and national guidelines for clinical practice.
References
Zhang R et al. Multi-omics analysis of patient-derived organoids reveals that E3 ligase COP1 promotes liver metastasis and oxaliplatin resistance in colorectal cancer through LUZP1 degradation and MYL9 phosphorylation. Exp Hematol Oncol. 2026 Apr 05. doi: 10.1186/s40164-026-00771-7. PMID: 41937206.
Wang J, et al. Integrative multi-omics of matched primary and liver metastatic colorectal cancer organoids identifies putative molecular targets. Transl Oncol. 2025;63:102592.
Chen L, et al. E3 ubiquitin ligase-dependent regulatory mechanism of TRIM family in carcinogenesis. Cancer Insight. 2023;2(2):21.
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COP1 promotes colorectal cancer liver metastasis and oxaliplatin resistance by degrading LUZP1 and activating the MYL9 pathway, identifying a new therapeuti...
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