Exosome-derived tRNA fragments tRF-GluCTC-0005 promotes pancreatic cancer liver metastasis by activating hepatic stellate cells
Abstract Early metastasis is the primary factor in the very poor prognosis of pancreatic ductal adenocarcinoma (PDAC), with liver metastasis being the most common form of distant metastasis in PDAC. To investigate the mechanism of PDAC liver metastasis, we found that PDAC cells can promote the forma...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2024-01-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-024-06482-3 |
| _version_ | 1797273022700191744 |
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| author | Wei Chen Wang Peng Ronghua Wang Shuya Bai Mengdie Cao Si Xiong Yanling Li Yilei Yang Jingwen Liang Luyao Liu Hamza O. Yazdani Yuchong Zhao Bin Cheng |
| author_facet | Wei Chen Wang Peng Ronghua Wang Shuya Bai Mengdie Cao Si Xiong Yanling Li Yilei Yang Jingwen Liang Luyao Liu Hamza O. Yazdani Yuchong Zhao Bin Cheng |
| author_sort | Wei Chen |
| collection | DOAJ |
| description | Abstract Early metastasis is the primary factor in the very poor prognosis of pancreatic ductal adenocarcinoma (PDAC), with liver metastasis being the most common form of distant metastasis in PDAC. To investigate the mechanism of PDAC liver metastasis, we found that PDAC cells can promote the formation of pre-metastatic niches (PMNs) through exosomes to facilitate liver metastasis in the early stage. In our study, hepatic stellate cells (HSCs) were treated with PDAC-derived exosomes (PDAC-exo), and the activation of HSCs was detected. A novel transfer RNA-derived fragment, the tRF-GluCTC-0005 was obtained by small RNA sequencing from serum exosomes of PDAC patients. Bioinformatics analysis and RNA pull-down assays revealed the interaction between WDR1 and tRF-GluCTC-0005. A KPC transgenic mouse model and an AAV-mediated sh-WDR1 mouse model were used to detect the mechanism of liver metastasis in vivo. Finally, the dual luciferase reporter assay, protein mutation truncation assay, Co-IP assay, and flow cytometry assay were used to explore the molecular mechanism in HSCs activation and PMNs formation. We found that the tRF-GluCTC-0005 in exosomes binds to the 3’ untranslated region of the mRNA of the WDRl in HSCs and increases mRNA stability. The N-terminals of WDR1 bind to the YAP protein directly, inhibit YAP phosphorylation, and promote the expression of YAP transcription factors. The tRF-GluCTC-0005 in PDAC-exo significantly recruits myeloid-derived suppressor cells (MDSCs) in the liver, creating a PMNs immunosuppressive microenvironment and further advancing liver metastasis from PDAC. Our results suggest that the key of PDAC liver metastasis is the activation of HSCs through upregulation of WDR1 by tRF-GluCTC-0005 in exosomes, which mediates the infiltration of MDSCs to form PMNs. |
| first_indexed | 2024-03-07T14:38:35Z |
| format | Article |
| id | doaj.art-26f926f59c53428984d25246a58aea95 |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-03-07T14:38:35Z |
| publishDate | 2024-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-26f926f59c53428984d25246a58aea952024-03-05T20:30:38ZengNature Publishing GroupCell Death and Disease2041-48892024-01-0115111710.1038/s41419-024-06482-3Exosome-derived tRNA fragments tRF-GluCTC-0005 promotes pancreatic cancer liver metastasis by activating hepatic stellate cellsWei Chen0Wang Peng1Ronghua Wang2Shuya Bai3Mengdie Cao4Si Xiong5Yanling Li6Yilei Yang7Jingwen Liang8Luyao Liu9Hamza O. Yazdani10Yuchong Zhao11Bin Cheng12Department of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Surgery, University of Pittsburgh School of MedicineDepartment of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Surgery, University of Pittsburgh School of MedicineDepartment of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyDepartment of Gastroenterology and Hepatology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Early metastasis is the primary factor in the very poor prognosis of pancreatic ductal adenocarcinoma (PDAC), with liver metastasis being the most common form of distant metastasis in PDAC. To investigate the mechanism of PDAC liver metastasis, we found that PDAC cells can promote the formation of pre-metastatic niches (PMNs) through exosomes to facilitate liver metastasis in the early stage. In our study, hepatic stellate cells (HSCs) were treated with PDAC-derived exosomes (PDAC-exo), and the activation of HSCs was detected. A novel transfer RNA-derived fragment, the tRF-GluCTC-0005 was obtained by small RNA sequencing from serum exosomes of PDAC patients. Bioinformatics analysis and RNA pull-down assays revealed the interaction between WDR1 and tRF-GluCTC-0005. A KPC transgenic mouse model and an AAV-mediated sh-WDR1 mouse model were used to detect the mechanism of liver metastasis in vivo. Finally, the dual luciferase reporter assay, protein mutation truncation assay, Co-IP assay, and flow cytometry assay were used to explore the molecular mechanism in HSCs activation and PMNs formation. We found that the tRF-GluCTC-0005 in exosomes binds to the 3’ untranslated region of the mRNA of the WDRl in HSCs and increases mRNA stability. The N-terminals of WDR1 bind to the YAP protein directly, inhibit YAP phosphorylation, and promote the expression of YAP transcription factors. The tRF-GluCTC-0005 in PDAC-exo significantly recruits myeloid-derived suppressor cells (MDSCs) in the liver, creating a PMNs immunosuppressive microenvironment and further advancing liver metastasis from PDAC. Our results suggest that the key of PDAC liver metastasis is the activation of HSCs through upregulation of WDR1 by tRF-GluCTC-0005 in exosomes, which mediates the infiltration of MDSCs to form PMNs.https://doi.org/10.1038/s41419-024-06482-3 |
| spellingShingle | Wei Chen Wang Peng Ronghua Wang Shuya Bai Mengdie Cao Si Xiong Yanling Li Yilei Yang Jingwen Liang Luyao Liu Hamza O. Yazdani Yuchong Zhao Bin Cheng Exosome-derived tRNA fragments tRF-GluCTC-0005 promotes pancreatic cancer liver metastasis by activating hepatic stellate cells Cell Death and Disease |
| title | Exosome-derived tRNA fragments tRF-GluCTC-0005 promotes pancreatic cancer liver metastasis by activating hepatic stellate cells |
| title_full | Exosome-derived tRNA fragments tRF-GluCTC-0005 promotes pancreatic cancer liver metastasis by activating hepatic stellate cells |
| title_fullStr | Exosome-derived tRNA fragments tRF-GluCTC-0005 promotes pancreatic cancer liver metastasis by activating hepatic stellate cells |
| title_full_unstemmed | Exosome-derived tRNA fragments tRF-GluCTC-0005 promotes pancreatic cancer liver metastasis by activating hepatic stellate cells |
| title_short | Exosome-derived tRNA fragments tRF-GluCTC-0005 promotes pancreatic cancer liver metastasis by activating hepatic stellate cells |
| title_sort | exosome derived trna fragments trf gluctc 0005 promotes pancreatic cancer liver metastasis by activating hepatic stellate cells |
| url | https://doi.org/10.1038/s41419-024-06482-3 |
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