biostudies-literatureMurthy DU.S. Department of Health & Human Services | NIH | National Cancer InstituteNCI NIH HHSNIGMS NIH HHS613-627https://www.ebi.ac.uk/biostudies/studies/S-EPMC11021164biostudies-literatureUnknown26(4)The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated aceNature cell biologyCancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.PMC11021164P30 CA036727U54CA274329P20 GM113126P50 CA127297P30 GM103335R01CA270234P20 GM121316R01 CA270234R01CA256911T32 CA009476R01 CA256911R01CA163649R01 CA163649R37 CA276924R37CA276924P20 GM103447U54 CA274329P30 CA225520R50 CA211462Rai VRana SKumar VHu TChaudhary SWellen KEThakur RWang DYu FKlinkebiel DLSouchek JBlack ARPacheco CNatarajan AJain ALazenby AJMehla KPatel RChaika NVHollingsworth MADasgupta AKollala SSKing RJShukla SKHe CGrandgenett PMSingh PKPowers RJha KMulder SEEdil BHMurthy DHwang RFAttri KSGebregiworgis TUlhannan SLy QfalseCancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated ace2024-01-01T00:00:00Z2024 Apr2026-05-29T17:47:28.142Z2026-04-08T05:45:23.258ZS-EPMC110211643842947810.1038/s41556-024-01372-4