m6A demethylase FTO drives pancreatic ductal adenocarcinoma tumorigenesis and metastasis through remodeling PFKM mediated glycolysis

Abstract N6-methyladenosine (m 6 A) modification has emerged as a common chemical modification in epigenetic regulation. However, whether this m 6 A modification is involved in glycolysis metabolism in pancreatic ductal adenocarcinoma (PDAC) remains elusive. Multiomics integration strategies, including metabolomics, m 6 A-seq and transcriptome sequencing, were utilized to evaluate the associations between m 6 A modifications and key processes of glucose metabolism in PDAC. Spontaneous PDAC mice (LSLKras G12D/+ , LSL-Trp53 R172H/+ , Pdx1-Cre; KPC) with FTO-conditional knockout and organoids were used to evaluate the effects of FTO stimulation on PDAC cell glycolysis and tumorigenesis. Series of in vivo and vitro functional analysis revealed that FTO promoted migratory capacity and glycolysis of PDAC cells. Mechanistically, FTO elevates the mRNA expression of the transcription factor C-Jun in a m 6 A-YTHDF2-dependent manner and further transcriptionally upregulates PFKM expression. Translational studies involving organoid models and xenograft tumor models revealed that the use of FTO inhibitors significantly suppressed PDAC growth. Our findings uncover that targeting the m 6 A-dependent FTO/C-Jun/PFKM glycolysis regulatory axis may be essential for the prevention and treatment of PDAC.