Exosomes derived from ccRCC cells confers fibroblasts activation to foster tumor progression through Warburg effect by downregulating PANK3
Abstract The interaction between tumor-derived exosomes and stroma plays a crucial role in tumor progression. However, the mechanisms through which tumor cells influence stromal changes are not yet fully understood. In our study, through single-cell sequencing analysis of clear cell renal cell carci...
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| Format: | Article |
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Nature Publishing Group
2025-04-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-025-02434-8 |
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| author | Yang Yang Cheng Qiang Zhu Jie Han Ce Huang Yan Li Xiu-bin Fan Wen-mei Zhang Xu Gao Yu |
| author_facet | Yang Yang Cheng Qiang Zhu Jie Han Ce Huang Yan Li Xiu-bin Fan Wen-mei Zhang Xu Gao Yu |
| author_sort | Yang Yang |
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| description | Abstract The interaction between tumor-derived exosomes and stroma plays a crucial role in tumor progression. However, the mechanisms through which tumor cells influence stromal changes are not yet fully understood. In our study, through single-cell sequencing analysis of clear cell renal cell carcinoma tissues at varying stages of progression, we determined that the proportion of cancer-associated fibroblasts (CAFs) in advanced renal cell carcinoma tissues was notably higher compared to localized renal cell carcinoma tissues. Comparison of transcriptome sequencing and energy metabolism tests between CAFs primarily isolated from advanced renal cell carcinoma tissues and normal fibroblasts (NFs) revealed the occurrence of the Warburg effect during the fibroblast activation process. Additionally, we observed an increase in glucose transporter GLUT1 expression, total reactive oxygen species (ROS) levels, lactic acid production, and subsequent excretion of excess lactic acid through monocarboxylate transporter-4 (MCT4) in CAFs. Interestingly, renal cancer cells were found to uptake lactic acid via MCT1 upon interaction with CAFs, thereby enhancing their malignant phenotypes. Furthermore, the down-regulation of PANK3 induced by exosomes derived from renal cancer cells was identified as a crucial step in fibroblast activation. These findings indicate that exosomes play a role in facilitating intercellular communication between renal cancer cells and fibroblasts. Targeting this communication pathway could potentially offer new strategies for the prevention and treatment of advanced renal cell carcinoma. |
| format | Article |
| id | doaj-art-86ec93234267405bba3dca9c2de8e914 |
| institution | OA Journals |
| issn | 2058-7716 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Nature Publishing Group |
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| series | Cell Death Discovery |
| spelling | doaj-art-86ec93234267405bba3dca9c2de8e9142025-08-20T02:19:55ZengNature Publishing GroupCell Death Discovery2058-77162025-04-0111111110.1038/s41420-025-02434-8Exosomes derived from ccRCC cells confers fibroblasts activation to foster tumor progression through Warburg effect by downregulating PANK3Yang Yang0Cheng Qiang1Zhu Jie2Han Ce3Huang Yan4Li Xiu-bin5Fan Wen-mei6Zhang Xu7Gao Yu8Department of Urology, the third Medical Centre, Chinese PLA General HospitalDepartment of Urology, the third Medical Centre, Chinese PLA General HospitalDepartment of Urology, the third Medical Centre, Chinese PLA General HospitalDepartment of Urology, the third Medical Centre, Chinese PLA General HospitalDepartment of Urology, the third Medical Centre, Chinese PLA General HospitalDepartment of Urology, the third Medical Centre, Chinese PLA General HospitalDepartment of Urology, the third Medical Centre, Chinese PLA General HospitalDepartment of Urology, the third Medical Centre, Chinese PLA General HospitalDepartment of Urology, the third Medical Centre, Chinese PLA General HospitalAbstract The interaction between tumor-derived exosomes and stroma plays a crucial role in tumor progression. However, the mechanisms through which tumor cells influence stromal changes are not yet fully understood. In our study, through single-cell sequencing analysis of clear cell renal cell carcinoma tissues at varying stages of progression, we determined that the proportion of cancer-associated fibroblasts (CAFs) in advanced renal cell carcinoma tissues was notably higher compared to localized renal cell carcinoma tissues. Comparison of transcriptome sequencing and energy metabolism tests between CAFs primarily isolated from advanced renal cell carcinoma tissues and normal fibroblasts (NFs) revealed the occurrence of the Warburg effect during the fibroblast activation process. Additionally, we observed an increase in glucose transporter GLUT1 expression, total reactive oxygen species (ROS) levels, lactic acid production, and subsequent excretion of excess lactic acid through monocarboxylate transporter-4 (MCT4) in CAFs. Interestingly, renal cancer cells were found to uptake lactic acid via MCT1 upon interaction with CAFs, thereby enhancing their malignant phenotypes. Furthermore, the down-regulation of PANK3 induced by exosomes derived from renal cancer cells was identified as a crucial step in fibroblast activation. These findings indicate that exosomes play a role in facilitating intercellular communication between renal cancer cells and fibroblasts. Targeting this communication pathway could potentially offer new strategies for the prevention and treatment of advanced renal cell carcinoma.https://doi.org/10.1038/s41420-025-02434-8 |
| spellingShingle | Yang Yang Cheng Qiang Zhu Jie Han Ce Huang Yan Li Xiu-bin Fan Wen-mei Zhang Xu Gao Yu Exosomes derived from ccRCC cells confers fibroblasts activation to foster tumor progression through Warburg effect by downregulating PANK3 Cell Death Discovery |
| title | Exosomes derived from ccRCC cells confers fibroblasts activation to foster tumor progression through Warburg effect by downregulating PANK3 |
| title_full | Exosomes derived from ccRCC cells confers fibroblasts activation to foster tumor progression through Warburg effect by downregulating PANK3 |
| title_fullStr | Exosomes derived from ccRCC cells confers fibroblasts activation to foster tumor progression through Warburg effect by downregulating PANK3 |
| title_full_unstemmed | Exosomes derived from ccRCC cells confers fibroblasts activation to foster tumor progression through Warburg effect by downregulating PANK3 |
| title_short | Exosomes derived from ccRCC cells confers fibroblasts activation to foster tumor progression through Warburg effect by downregulating PANK3 |
| title_sort | exosomes derived from ccrcc cells confers fibroblasts activation to foster tumor progression through warburg effect by downregulating pank3 |
| url | https://doi.org/10.1038/s41420-025-02434-8 |
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