{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE305nnn/GSE305529/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":[" Other","Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE305529"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"METTL3-Driven RNA Modifications: A Key Mechanism and Potential Therapeutic Target in Pancreatic Acinar Cell Carcinoma in Mice [MeRIP]","description":"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.","dates":{"publication":"2026/04/12"},"accession":"GSE305529","cross_references":{"GSM":["GSM9178859","GSM9178879","GSM9178857","GSM9178858","GSM9178884","GSM9178862","GSM9178885","GSM9178863","GSM9178882","GSM9178860","GSM9178861","GSM9178883","GSM9178888","GSM9178866","GSM9178867","GSM9178889","GSM9178864","GSM9178886","GSM9178887","GSM9178865","GSM9178880","GSM9178881","GSM9178868","GSM9178869","GSM9178895","GSM9178873","GSM9178852","GSM9178896","GSM9178874","GSM9178893","GSM9178871","GSM9178872","GSM9178894","GSM9178855","GSM9178899","GSM9178877","GSM9178878","GSM9178856","GSM9178875","GSM9178853","GSM9178897","GSM9178898","GSM9178876","GSM9178854","GSM9178891","GSM9178892","GSM9178870","GSM9178890"],"GPL":["17021"],"GSE":["305529"],"taxon":["Mus musculus"]}}