期刊
CANCER RESEARCH
卷 81, 期 1, 页码 64-76出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-20-0256
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资金
- National Natural Science Foundation of China [81370068, 81572376, 81622049, 81871989]
- Shanghai Science and Technology Committee Program [19XD1420900]
- Shanghai Education Commission Program [17SG04]
- Shanghai Municipal Health Commission program [ZY(2018-2020)-CCCX-2005]
This study uncovered a Notch-dependent feedback circuit between pancreatic cancer cells and macrophages, which promotes PDAC metastasis through miR-124, IL6, and STAT3 signaling pathways. Disrupting this circuit could potentially be a therapeutic approach for treating PDAC metastasis.
Notch activation has been detected in pancreatic ductal adenocarcinoma (PDAC). However, its role in PDAC metastasis remains unknown. In this study, we identify a Notch-dependent feedback circuit between pancreatic cancer cells and macrophages, which contributes to PDAC metastasis. In this circuit, miR-124 regulated Notch signaling in cancer cells by directly targeting the Notch ligand Jagged 1. Autoamplified Notch signaling promoted the recruitment and activation of macrophages to a tumor-supporting M2-like phenotype via downstream IL8, CCL2, IL1 alpha, and uPA paracrine signaling. In turn, activated macrophage-derived IL6 activated the oncogenic transcription factor STAT3 that directly repressed miR-124 genes via a conserved STAT3-binding site in their promoters, thereby promoting cancer cell epithelial-mesenchymal transition and invasion. Disrupting this circuit suppressed liver metastasis in mouse models. Thus, our study suggests that manipulation of this Notch-dependent circuit has a therapeutic potential for the treatment of PDAC metastasis. Significance: This study provided potential therapeutic targets and robust preclinical evidence for PDAC treatment by interrupting feedback signaling between cancer cells and macrophages with targeted inhibitors.
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