Extracellular Vesicle-Packaged circTAX1BP1 from Cancer-Associated Fibroblasts Regulates RNA m6A Modification through Lactylation of VIRMA in Colorectal Cancer Cells

Abstract

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.

Keywords: cancer‐associated fibroblasts; circRNAs; colorectal cancer; extracellular vesicles; tumor microenvironment.