LMO3 is a suppressor of the basal-like/squamous PDAC subtype and reduces disease aggressiveness of pancreatic cancer through glycerol 3-phosphate metabolism

Abstract

AbstractPancreatic ductal adenocarcinoma (PDAC) encompasses diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, each exhibiting distinct characteristics, with the latter known for its aggressiveness. We employed an integrative approach combining transcriptomic and metabolomic analyses to pinpoint potential genes contributing to the basal-like/squamous subtype differentiation. Applying this approach to our NCI-UMD-German and a validation cohort, we identified LIM Domain Only 3 (LMO3), a transcription co-factor, as a candidate suppressor of the basal-like/squamous subtype. Reduced LMO3 expression was significantly associated with higher pathological grade, advanced disease stage, induction of the basal-like/squamous subtype, and decreased survival among PDAC patients.In vitroexperiments demonstrated thatLMO3transgene expression inhibited PDAC cell proliferation and migration/invasion, concurrently downregulating the basal-like/squamous gene signature. Metabolomic analysis of patient tumors and PDAC cells revealed a metabolic program linked to elevated LMO3 expression and the classical/progenitor subtype, characterized by enhanced lipogenesis and suppressed amino acid metabolism. Notably, glycerol 3-phosphate (G3P) levels positively correlated with LMO3 expression and associated with improved patient survival. Furthermore, glycerol-3-phosphate dehydrogenase 1 (GPD1), a crucial enzyme in G3P synthesis, showed upregulation in LMO3-high and classical/progenitor PDAC, suggesting its potential role in mitigating disease aggressiveness. Collectively, our findings suggest that heightened LMO3 expression reduces transcriptomic and metabolomic characteristics indicative of basal-like/squamous tumors with decreased disease aggressiveness in PDAC patients. The observations describe LMO3 as a candidate for diagnostic and therapeutic targeting in PDAC.Graphical abstractHighlightsLMO3 is downregulated in basal-like/squamous PDAC while its expression is maintained in the classical/progenitor PDAC subtypeUpregulated LMO3 expression correlates with improved PDAC survival and reduced proliferation and migration/invasion in PDAC cellsUpregulated LMO3 suppresses basal-like/squamous differentiation and induces a unique metabolic signature characterized by elevated lipogenesis and diminished amino acid metabolism, resembling the classical/progenitor PDAC subtypeEnhanced LMO3 expression associates with elevated glycerol 3-phosphate levels in PDAC, correlating with improved patient survival in PDAC