METTL3-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.