Targeting sulfatide metabolism as a therapeutic vulnerability in pancreatic pre-cancer lesions

Asymptomatic precursor lesions that predate invasive pancreatic ductal adenocarcinoma (PDAC) by years provide a compelling opportunity for cancer interception. One such precursor is the intraductal papillary mucinous neoplasm (IPMN). Using Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry (MALDI-MS) imaging and spatial transcriptomics, we discovered long-chain hydroxylated sulfatide species and their biosynthetic enzymes as selectively enriched in IPMN. Genetic ablation of UGT8 and Gal3st1, the key enzymes catalyzing the synthesis of the sulfatide precursor galactosylceramide (GalCer) and sulfatides, respectively, suppressed sulfatide production and triggered mitochondrial ceramide accumulation in mutant Kras;Gnas IPMN cells. These metabolic disruptions led to reduced proliferation and invasiveness, alongside increased caspase-dependent apoptosis. Pharmacologic UGT8 inhibition also caused profound impairments in mitochondrial function and morphology. Integrated lipidomic and proteomic analyses on mitochondrial fractions revealed remodeling of lipid composition and dysregulation of proteins involved in mitochondrial translation, oxidative phosphorylation, mitophagy and sphingolipid metabolism, corroborating the phenotypic changes observed in our functional studies. In vivo, UGT8 inhibition suppressed tumor growth in IPMN allograft models. Collectively, our findings identify enhanced sulfatide metabolism as an early metabolic alteration of cystic pre-cancerous lesions and demonstrate that targeting UGT8 perturbs mitochondrial homeostasis and function, revealing a potential strategy for pancreatic cancer interception.