GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE297nnn/GSE297264/primaryOK200OtherHomo sapiensOtherhttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE297264GEOGSEfalseTRMT5/NES Coordinated Activity Drives Pancreatic Cancer Growth and Metastasis [RIP-seq I]Pancreatic cancer is a disease of urgent unmet clinical need with a 94% death rate, predicted to become the second leading cause of cancer-related death by 2030. Despite increased efforts, effective therapies have not materialised. Here, we uncover a new molecular pathway underpinning pancreatic carcinogenesis, involving TRMT5, an RNA m1G methyltransferase. We show that TRMT5 is overexpressed in primary pancreatic adenocarcinomas (PDACs), and its expression is associated with worse patient survival. High levels of TRMT5 expression positively correlate with the tumorigenic capacity of pancreatic cell lines and of human pancreatic cancer organoids. Using an unbiased multiple screening approach, we identify a new axis involving TRMT5 and Nestin (NES) in pancreatic cancer and define NES mRNA as a substrate of TRMT5. We demonstrate that NES expression, a key cancer regulator, rescues the growth defect of TRMT5 depleted PDAC cells. We pinpoint a site of TRMT5-mediated m1G modification to a G-quadruplex structure within the protein coding region of NES mRNA. Functionally, m1G destabilizes the G-quadruplex structure to promote translation of NES. Finally, we demonstrate that TRMT5 is essential for the metastatic capacity of PDAC cells, significantly promotes the growth of patient-derived PDAC organoids and increases the survival rate of PDAC patient-derived xenografts. Our findings establish the TRMT5/NES axis as a new vulnerability in PDAC and they provide the foundation for innovative combinatorial clinical approaches, targeting an RNA-modification pathway in pancreatic cancer.2026/05/04GSE297264GSM8987260GSM8987261GSM8987262GSM8987263GSM8987264GSM898725924676297264Homo sapiens