GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE305nnn/GSE305529/primaryOK200TranscriptomicsMus musculus OtherExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE305529GEOGSEfalseMETTL3-Driven RNA Modifications: A Key Mechanism and Potential Therapeutic Target in Pancreatic Acinar Cell Carcinoma in Mice [MeRIP]Pancreatic acinar cell carcinoma (ACC) represents a rare and aggressive malignancy with poorly understood molecular mechanisms. N6-methyladenosine (m6A) RNA modification, particularly through the methyltransferase METTL3, has emerged as a critical regulator in various cancers. This study investigates the role of METTL3-mediated RNA methylation in ACC development and progression. We utilized transgenic mouse models over-expressing Mettl3 and SV40 large T antigen under the pancreatic Elastase I promoter. Comprehensive analyses included m6A-methylated RNA immunoprecipitation sequencing (MeRIP-seq), single-cell RNA sequencing (scRNA-seq), and functional studies with the METTL3 inhibitor STM2457. SAM-binding domain deletion mutants were generated to assess functional requirements. Mettl3 overexpression significantly accelerated ACC development and enhanced tumor aggressiveness. The SAM-binding domain proved essential for tumor formation, as deletion mutants failed to promote carcinogenesis. MeRIP-seq revealed preferential methylation of cell cycle and DNA replication genes in Mettl3-overexpressing tumors. scRNA-seq analysis demonstrated enhanced malignancy signatures, including epithelial-to-mesenchymal transition and TGF-β signaling. METTL3 promoted PRSS1-mediated signaling from ACC cells to inflammatory cancer-associated fibroblasts, creating a feed-forward loop involving IGF1 that amplifies tumor growth. Conditional Mettl3 deletion induced rapid tumor apoptosis. Pharmacological inhibition with STM2457 similarly triggered caspase-3/7-dependent apoptosis in pancreatic tumors. METTL3-mediated RNA methylation drives ACC pathogenesis through tumor-intrinsic cell cycle regulation and tumor-extrinsic stromal interactions. These findings establish METTL3 as a promising therapeutic target and provide mechanistic insights supporting clinical development of METTL3 inhibitors for pancreatic cancer treatment.2026/04/12GSE305529GSM9178859GSM9178879GSM9178857GSM9178858GSM9178884GSM9178862GSM9178885GSM9178863GSM9178882GSM9178860GSM9178861GSM9178883GSM9178888GSM9178866GSM9178867GSM9178889GSM9178864GSM9178886GSM9178887GSM9178865GSM9178880GSM9178881GSM9178868GSM9178869GSM9178895GSM9178873GSM9178852GSM9178896GSM9178874GSM9178893GSM9178871GSM9178872GSM9178894GSM9178855GSM9178899GSM9178877GSM9178878GSM9178856GSM9178875GSM9178853GSM9178897GSM9178898GSM9178876GSM9178854GSM9178891GSM9178892GSM9178870GSM917889017021305529Mus musculus