METTL1 relays the tumor-promoting signal flow from senescent CAFs by modulating RNA m7G modifications with SASP-related cytokines

Colorectal cancer (CRC) remains a significant contributor to global cancer-related mortality. The significant role of senescent cancer-associated fibroblasts (S-CAFs) in the progression of CRC has been acknowledged, while the mechanisms remain unclear. We employed RNA sequencing, m7G-MeRIP sequencing, and Luminex liquid suspension chip assays to elucidate the epigenetic changes induced by S-CAFs. Our findings revealed a significant downregulation of METTL1 in CRC tissues, particularly in older patients, which correlates with poor prognosis. S-CAFs modulate METTL1 expression and m7G methylation, leading to epigenetic reprogramming that enhances tumor proliferation and invasion. The secretion of SASP cytokines PDGF-BB and TNF-a by S-CAFs was identified as key mediators of this process. The use of inhibitors such as rapamycin, Typhostin, and Infliximab demonstrated the potential to reverse epigenetic changes and inhibit CRC progression. Our study investigated the role of METTL1-mediated transcriptome reprogramming in the crosstalk between cancer cells and S-CAFs, offering novel insights into the complex mechanisms underlying tumor progression and providing a foundation for developing targeted therapies. Furthermore, our research paved the way for innovative therapeutic strategies that may improve outcomes for CRC patients, especially those with early-onset disease. Overall design: Total RNA was collected from DLD1 cells co-cultured with S-CAFs, DLD1 cells co-cultured with CAFs, DLD1 cells with stable METTL1-knockdown and control cells (two replications, which were labeled as sh2 and shnc, respectively) using TRIzol reagent (Invitrogen, CA).