RNA methyltransferase 3 drives pancreatic acinar cell carcinoma growth and is a therapeutic target

Pancreatic acinar cell carcinoma (ACC) is a rare and aggressive malignancy whose molecular basis remains poorly understood. N6-methyladenosine (m⁶A) RNA modification, mediated particularly through methyltransferase 3 (METTL3), has emerged as a critical regulator in various cancers. Here, we investigated the role of METTL3-mediated RNA methylation in ACC development and progression. We used transgenic mouse models overexpressing 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), functional studies using the METTL3 inhibitor STM2457, and S-adenosylmethionine (SAM)-binding domain deletion mutants to assess functional requirements. Mettl3 overexpression significantly accelerated ACC development and increased tumor aggressiveness. The SAM-binding domain was 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 transforming growth factor-β signaling. METTL3 also 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 the clinical development of METTL3 inhibitors for ACC treatment.