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The METTL3/TGF-β1 signaling axis promotes osteosarcoma progression by inducing MSC differentiation into CAFs via m6A modification

Year: 2025
Type: article
Abstract: • Osteosarcoma cells can induce MSCs differentiate into CAFs. • TGF-β1 promotes osteosarcoma cells-induced differentiation from MSCs into CAFs. • METTL3 promotes osteosarcoma cells-induced MSCs self-differentiation to CAFs by mediating m 6 A modification of TGF-β1 mRNA. • METTL3/TGF-β1 signaling axis facilitates MSCs-mediated osteosarcoma progression. Osteosarcoma, a prevalent and aggressive skeletal malignancy, significantly impacts the prognosis of individuals, particularly young patients. Current treatments, including surgery and chemotherapy, often prove inadequate for advanced osteosarcoma with metastasis. This study investigates the role of the METTL3/TGF-β1 signaling axis in promoting osteosarcoma progression by inducing mesenchymal stem cells (MSCs) to differentiate into cancer-associated fibroblasts (CAFs). Utilizing co-culture technology, we demonstrated that osteosarcoma cells secrete TGF-β1, which is crucial for MSC differentiation into CAFs, as evidenced by the increased expression of CAF markers α-SMA, FSP-1, and FAP. Additionally, METTL3 was found to enhance the stability and expression of TGF-β1 mRNA through m 6 A modification, thereby facilitating the differentiation process of MSCs. In vivo xenograft experiments further confirmed that the METTL3/TGF-β1 axis significantly promotes tumor growth in osteosarcoma by mediating the differentiation of MSCs into CAFs. These findings provide new insights into the molecular mechanisms underlying osteosarcoma progression and highlight potential therapeutic targets for treating advanced stages of this malignancy.
DOI: 10.1016/j.jbo.2025.100662
Language: English
Field: Medicine
Open Access status: gold
Estimated APC paid: $2,990
OpenAlex ID: W4407312749
FWCI: 3.523
Cites: 48
Cited by: 6
Related to: 10