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Updated: Apr 16, 2026
Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
Published on: January 12, 2020
Notch suppresses angiogenesis and progression of hepatic metastases
Debarshi Banerjee1, Sonia L Hernandez1, Alejandro Garcia2
1Department of Pediatrics, Columbia University Medical Center, New York, New York.
Abstract:
The Notch pathway plays multiple key roles in tumorigenesis, and its signaling components have therefore aroused great interest as targets for emerging therapies. Here, we show that inhibition of Notch, using a soluble receptor Notch1 decoy, unexpectedly caused a remarkable increase in liver metastases from neuroblastoma and breast cancer cells. Increased liver metastases were also seen after treatment with the γ-secretase inhibitor PF-03084014. Transgenic mice with heterozygous loss of Notch1 demonstrated a marked increase in hepatic metastases, indicating that Notch1 signaling acts as metastatic suppressor in the liver microenvironment. Inhibition of DLL1/4 with ligand-specific Notch1 decoys increased sprouting of sinusoidal endothelial cells into micrometastases, thereby supporting early metastatic angiogenic growth. Inhibition of tumor-derived JAG1 signaling activated hepatic stellate cells, increasing their recruitment to vasculature of micrometastases, thereby supporting progression to macrometastases. These results demonstrate that inhibition of Notch causes pathologic activation of liver stromal cells, promoting angiogenesis and growth of hepatic metastases. Our findings have potentially serious implications for Notch inhibition therapy.
Insights
Inhibiting the Notch pathway unexpectedly increased liver metastases in neuroblastoma and breast cancer. Notch1 signaling normally suppresses liver metastasis, and its inhibition promotes tumor growth and spread.
Area of Science:
- Oncology
- Cell Biology
- Cancer Metastasis
Background:
- The Notch pathway is crucial in tumorigenesis and a target for cancer therapies.
- Understanding Notch signaling's role in metastasis is essential for effective treatment strategies.
Purpose of the Study:
- To investigate the role of Notch signaling in liver metastasis of neuroblastoma and breast cancer.
- To evaluate the impact of Notch pathway inhibition on metastatic progression in the liver microenvironment.
Main Methods:
- Utilized a soluble receptor Notch1 decoy and a γ-secretase inhibitor (PF-03084014) to inhibit Notch signaling.
- Employed transgenic mice with heterozygous Notch1 loss to study its suppressive function.
- Investigated the effects of inhibiting DLL1/4 and tumor-derived JAG1 signaling on liver metastasis.
Main Results:
- Notch inhibition significantly increased liver metastases in neuroblastoma and breast cancer models.
- Notch1 acts as a metastatic suppressor in the liver microenvironment.
- Inhibition of Notch signaling promoted angiogenesis and hepatic stellate cell activation, facilitating metastatic growth.
Conclusions:
- Notch pathway inhibition can paradoxically promote liver metastasis by activating liver stromal cells and enhancing angiogenesis.
- These findings suggest potential adverse implications for Notch inhibition therapies in cancer treatment.
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