CAF-derived exosomes drive the FGF4/SHH feedback loop by encapsulating GREM1 in non-small cell lung cancer
Abstract Background One of the hallmarks of a pre-metastatic niche (PMN) is the infiltration of immunosuppressive macrophages, while the mechanism remains largely uncharted. Here, we reveal that cancer-associated fibroblasts-derived exosomes (CAF-exo) polarize macrophages towards an immunosuppressiv...
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BMC
2025-08-01
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| Series: | Molecular Medicine |
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| Online Access: | https://doi.org/10.1186/s10020-025-01340-0 |
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| author | Xianqiao Wu Wei Chen Tianzheng Fang Ziyuan Chen Shuai Fang Chengwei Zhou |
| author_facet | Xianqiao Wu Wei Chen Tianzheng Fang Ziyuan Chen Shuai Fang Chengwei Zhou |
| author_sort | Xianqiao Wu |
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| description | Abstract Background One of the hallmarks of a pre-metastatic niche (PMN) is the infiltration of immunosuppressive macrophages, while the mechanism remains largely uncharted. Here, we reveal that cancer-associated fibroblasts-derived exosomes (CAF-exo) polarize macrophages towards an immunosuppressive phenotype through encapsulating Gremlin-1 (GREM1) in non-small cell lung cancer (NSCLC). Methods CAF and normal fibroblasts (NF) were extracted from NSCLC patients, and the exosomes produced were extracted. The effects of NF- or CAF-derived exosomes on the expression of PMN-associated markers and macrophage M2 polarization markers in mouse lung and liver tissues were compared. CAF-exo-mediated macrophage phenotypic switching and immunosuppressive effects on T cells were studied in vitro. Orthotopic lung tumors were formed in mice using Lewis lung carcinoma (LLC) cells, followed by CAF-exo treatment. CAF-exo with GREM1 knockdown were used to treat macrophages or the LLC model mice. Finally, the reciprocal regulation between GREM1 and FGF4/SHH in macrophages was revealed, and rescue experiments were conducted. Results Intravenous injection of CAF-exo induced an immunosuppressive phenotype of macrophages in lung and liver tissues, leading to PMN formation. Tumor progression promoted by CAF-exo was blocked by knocking down GREM1 in CAF-exo. CAF-exo-derived GREM1 activated FGF4/SHH signaling in macrophages, and knockdown of FGF4/SHH inhibited macrophage M2 polarization. Ectopic expression of SHH or FGF4 activated GREM1/FGF4/SHH signaling and rescued the anti-tumor effects of GREM1 knockdown in vivo. Conclusions CAF-exo activated the positive feedback regulation of FGF4/SHH and GREM1 in macrophages by carrying GREM1, leading to the switch of macrophages to an immunosuppressive phenotype and PMN formation in NSCLC. |
| format | Article |
| id | doaj-art-5d0a7a2cef7c4d268a4d51b465d56a96 |
| institution | Kabale University |
| issn | 1528-3658 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | BMC |
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| series | Molecular Medicine |
| spelling | doaj-art-5d0a7a2cef7c4d268a4d51b465d56a962025-08-24T11:35:08ZengBMCMolecular Medicine1528-36582025-08-0131111910.1186/s10020-025-01340-0CAF-derived exosomes drive the FGF4/SHH feedback loop by encapsulating GREM1 in non-small cell lung cancerXianqiao Wu0Wei Chen1Tianzheng Fang2Ziyuan Chen3Shuai Fang4Chengwei Zhou5Department of Thoracic Surgery, The First Affiliated Hospital of Ningbo UniversityHealth Science Center, Ningbo UniversityHealth Science Center, Ningbo UniversityHealth Science Center, Ningbo UniversityDepartment of Thoracic Surgery, The First Affiliated Hospital of Ningbo UniversityDepartment of Thoracic Surgery, The First Affiliated Hospital of Ningbo UniversityAbstract Background One of the hallmarks of a pre-metastatic niche (PMN) is the infiltration of immunosuppressive macrophages, while the mechanism remains largely uncharted. Here, we reveal that cancer-associated fibroblasts-derived exosomes (CAF-exo) polarize macrophages towards an immunosuppressive phenotype through encapsulating Gremlin-1 (GREM1) in non-small cell lung cancer (NSCLC). Methods CAF and normal fibroblasts (NF) were extracted from NSCLC patients, and the exosomes produced were extracted. The effects of NF- or CAF-derived exosomes on the expression of PMN-associated markers and macrophage M2 polarization markers in mouse lung and liver tissues were compared. CAF-exo-mediated macrophage phenotypic switching and immunosuppressive effects on T cells were studied in vitro. Orthotopic lung tumors were formed in mice using Lewis lung carcinoma (LLC) cells, followed by CAF-exo treatment. CAF-exo with GREM1 knockdown were used to treat macrophages or the LLC model mice. Finally, the reciprocal regulation between GREM1 and FGF4/SHH in macrophages was revealed, and rescue experiments were conducted. Results Intravenous injection of CAF-exo induced an immunosuppressive phenotype of macrophages in lung and liver tissues, leading to PMN formation. Tumor progression promoted by CAF-exo was blocked by knocking down GREM1 in CAF-exo. CAF-exo-derived GREM1 activated FGF4/SHH signaling in macrophages, and knockdown of FGF4/SHH inhibited macrophage M2 polarization. Ectopic expression of SHH or FGF4 activated GREM1/FGF4/SHH signaling and rescued the anti-tumor effects of GREM1 knockdown in vivo. Conclusions CAF-exo activated the positive feedback regulation of FGF4/SHH and GREM1 in macrophages by carrying GREM1, leading to the switch of macrophages to an immunosuppressive phenotype and PMN formation in NSCLC.https://doi.org/10.1186/s10020-025-01340-0Non-small cell lung cancerPre-metastatic nicheCancer-associated fibroblastMacrophage polarizationGREM1 |
| spellingShingle | Xianqiao Wu Wei Chen Tianzheng Fang Ziyuan Chen Shuai Fang Chengwei Zhou CAF-derived exosomes drive the FGF4/SHH feedback loop by encapsulating GREM1 in non-small cell lung cancer Molecular Medicine Non-small cell lung cancer Pre-metastatic niche Cancer-associated fibroblast Macrophage polarization GREM1 |
| title | CAF-derived exosomes drive the FGF4/SHH feedback loop by encapsulating GREM1 in non-small cell lung cancer |
| title_full | CAF-derived exosomes drive the FGF4/SHH feedback loop by encapsulating GREM1 in non-small cell lung cancer |
| title_fullStr | CAF-derived exosomes drive the FGF4/SHH feedback loop by encapsulating GREM1 in non-small cell lung cancer |
| title_full_unstemmed | CAF-derived exosomes drive the FGF4/SHH feedback loop by encapsulating GREM1 in non-small cell lung cancer |
| title_short | CAF-derived exosomes drive the FGF4/SHH feedback loop by encapsulating GREM1 in non-small cell lung cancer |
| title_sort | caf derived exosomes drive the fgf4 shh feedback loop by encapsulating grem1 in non small cell lung cancer |
| topic | Non-small cell lung cancer Pre-metastatic niche Cancer-associated fibroblast Macrophage polarization GREM1 |
| url | https://doi.org/10.1186/s10020-025-01340-0 |
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