ArticleMolecular medicine (Cambridge, Mass.)2025
CAF-derived exosomes drive the FGF4/SHH feedback loop by encapsulating GREM1 in non-small cell lung cancer.
Article in Molecular medicine (Cambridge, Mass.), 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 3 papers.
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Who cites it
3 citing papers in PubMed.
- Integrative transcriptomic and experimental analysis identifies GREM1 as a pro-metastatic mediator in lung adenocarcinoma.Journal of translational medicine · 2026Article
- Review
- Fibroblasts as a ruler of the immune microenvironment: measurement and modulation in tissue homeostasis and disease.Frontiers in immunology · 2025Review
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Authors and funding
6 authors.
Funding
Abstract
backgroundOne 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).
methodsCAF 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.
resultsIntravenous 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.
conclusionsCAF-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.
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