Shotaro Tatekawa, Tomoaki Hara, Sikun Meng, Tetsuya Sato, Takahiro Arai, Keisuke Tamari, Yasuko Arao, Yoshiko Tsuji, Masamitsu Konno, Ken Ofusa, Koji Kitamura, Sarah Rennie, Motoharu Inui, Daisuke Taguchi, Hirofumi Akita, Daisuke Motooka, Yoshiki Murakumo, Hidenori Inohara, Yuichiro Doki, Hidetoshi Eguchi, Kazuhiko Ogawa, Hideshi Ishii
Used transgenic mouse models overexpressing Mettl3 and SV40 large T antigen under the pancreatic elastase I promoter for comprehensive analyses including 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. Mettl3 overexpression significantly accelerated ACC development and increased tumor aggressiveness; the SAM-binding domain was essential for tumor formation; 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-mediated RNA methylation drives ACC pathogenesis through tumor-intrinsic cell cycle and promotes 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 and pharmacological inhibition with STM2457 triggered caspase-3/7-dependent apoptosis in pancreatic tumors.
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.