Extracellular Vesicle-Packaged circTAX1BP1 from Cancer-Associated Fibroblasts Regulates RNA m6A Modification through...

The underlying molecular mechanism of patients with colorectal liver metastasis (CRLM) remains unclear. In this study, it is found that cancer-associated fibroblasts (CAFs)-derived extracellular vesicles (EVs) are significantly enriched in circTAX1BP1 in CRLM, which associate with poor prognosis. The disruption of EV-packaged circTAX1BP1 significantly inhibits CRLM in vivo and in vitro. Mechanistically, CAF-derived EV-packaged circTAX1BP1 is delivered to colorectal cancer (CRC) cells, where it binds to VIRMA and promotes its lactylation at lysine residue 1713 by recruiting AARS2. Lactylated VIRMA enhances m⁶A-based modification and stability of SP1 mRNA. SP1 mediates the transcription of TGF-β, enhancing epithelial-mesenchymal transition and paracrine TGF-β of CRC cells. Notably, this study identifies an important subgroup ITGA11⁺ myCAFs through single-cell RNA sequencing data. Paracrine TGF-β of CRC cells specifically targets ITGA11⁺ myCAFs, activating the TGF-β signalling pathway, which contributes to extracellular matrix remodeling and increases delivery of EV-packaged circTAX1BP1, forming a positive feedback loop to promote CRLM. Finally, the combined blockade of EV-packaged circTAX1BP1 and TGF-β can effectively disrupt this feedback loop and significantly inhibit tumor progression in a PDX model. Overall, this study provides an in-depth understanding of tumor cell-CAFs crosstalk and new insights into therapeutic targets for CRLM.