The cellular origin of hepatocellular carcinomas (HCC) and the role of Notch1 signalling in HCC initiation are controversial. Herein, we establish Notch1 as a regulator of HCC development and progression. Clinically, high Notch1 expression correlates with enhanced cancer progression, elevated lung metastasis, increased cancer stem cell (CSC)-like cells’ gene signature expression, and poor overall survival in HCC patients. Notch1 intracellular domain (N1ICD) overexpression spontaneously transforms rat liver progenitor cells (LPC) into CSC-like cells (WBN1ICD C5) under a selective growth environment, while orthotopic injection of these cells generates liver tumors and spontaneous pulmonary metastasis in an isogenic rat model. Mechanistically, the elevated Notch1 activity increases c-myc expression, which then transcriptionally upregulates VCAM1 expression to activate macrophage dependent HCC transendothelial migration. In vivo, silencing c-myc prohibits the tumorigenicity of WBN1ICD C5 cells, while depletion of VCAM1 reduces spontaneous lung metastasis without affecting primary WBN1ICD C5 orthotopic liver tumor growth. Importantly, depletion of macrophage or blockade of macrophage VCAM1 binding receptor α4β1-integrin reduces the number of WBN1ICD C5 lung nodules in an experimental metastasis model. Overall, our work discovers that the Notch1-c-myc-VCAM1 signaling axis initiates LPC-driven hepatocarcinogenesis and metastasis, providing a preclinical model for HCC study and therapeutic targets for an improved HCC treatment.
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All the data supporting the findings of this study are available within the article and its supplementary information files and from the corresponding author upon reasonable request.
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Some of the illustrations were created using Biorender.com. This work was supported by grants from the National Natural Science Foundation of China (81972255, 82173195, 81920108028, 81872142, 81772597, 82173229, 81702904, 81972262), Guangdong Natural Science Foundation (2021A1515010095, 712055485047), Guangzhou Science and Technology Program Key Project (201904020008), Sun Yat-sen University Clinical Research 5010 Program (2018008), Science and Technology Program of Guangzhou (202102010326), Sun Yat-sen University Fundamental Research Funds (19ykpy113), the Key Training Program for Young Scholars of Sun Yat-sen University (18ykzd07), grant from the Key Laboratory of Malignant Tumor Molecular Mechanism and Translational Medicine of Guangzhou Bureau of Science and Information Technology (163), the Key Laboratory of Malignant Tumor Gene Regulation and Target Therapy of Guangdong Higher Education Institutes (KLB09001), Guangdong Science and Technology Department (2020A0505100029, 2020B1212060018, 2020B1212030004), the Guangdong Translational Medicine Public Platform of Guangdong Province (4202037).
The authors declare no competing interests.
All animal procedures were approved by the animal care and use committee of Sun Yat-sen University.
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Wu, WR., Shi, XD., Zhang, FP. et al. Activation of the Notch1-c-myc-VCAM1 signalling axis initiates liver progenitor cell-driven hepatocarcinogenesis and pulmonary metastasis. Oncogene 41, 2340–2356 (2022). https://doi.org/10.1038/s41388-022-02246-5