Selective Dependence on Stromal Acetate induced Polyamine Metabolism Provides Unique Therapeutic Opportunities in Pancreatic Cancer

ABSTRACT: The ability of tumor cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. However, the signaling and nutritional potential of the stromal cell-secreted metabolites remains poorly understood. We identified a novel metabolic crosstalk between cancer associated fibroblasts (CAFs) and pancreatic cancer cells. We demonstrate that pancreatic CAFs regulate tumor cell metabolism through the secretion of acetate, which can be blocked by silencing ACLY in CAFs. Cancer cells present a unique dependence on CAF-derived acetate under acidosis. We further show that ACSS2 channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in the 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 observed novel acetate/ACSS2-mediated acetylation of SP1 at lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished tumor burden in mouse models. Increased SAT1-mediated production of N1-acetylspermidine correlated with disease progression in the spontaneous tumor progression model and poor survival in cancer patients. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.

INSTRUMENT(S): Orbitrap Fusion Lumos

ORGANISM(S): Homo Sapiens (ncbitaxon:9606)

SUBMITTER: Pankaj K Singh  

PROVIDER: MSV000093165 | MassIVE | Fri Oct 20 12:33:00 BST 2023

SECONDARY ACCESSION(S): PXD046270

REPOSITORIES: MassIVE