ELAPOR1 induces the classical/progenitor subtype and contributes to reduced disease aggressiveness through metabolic reprogramming in pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes classified as classical/progenitor and basal-like/squamous. We hypothesized that integrative transcriptomic and metabolomic approaches can identify candidate genes whose inactivation contributes to the development of the aggressive basal-like/squamous subtype. Using our integrated approach, we identified endosome-lysosome associated apoptosis and autophagy regulator 1 (ELAPOR1/KIAA1324) as a candidate tumor suppressor in both our NCI-UMD-German cohort and validation cohorts. We found that decreased ELAPOR1 expression was significantly associated with high pathological grade, advanced disease stage, the basal-like/squamous subtype, and decreased survival in PDAC patients. In vitro experiments showed that ELAPOR1 transgene expression inhibited migration and invasion of PDAC cells. Metabolomic analysis of patient tumors and PDAC cells revealed a metabolic program associated with both upregulated ELAPOR1 and the classical/progenitor subtype, encompassing upregulated lipogenesis and downregulated amino acid metabolism. 1-methylnicotinamide, an oncometabolite derived from S-adenosylmethionine, was inversely associated with ELAPOR1 expression and promoted migration and invasion of PDAC cells in vitro. Taken together, our data suggest that enhanced ELAPOR1 expression promotes transcriptomic and metabolomic characteristics that are indicative of the classical/progenitor subtype, whereas its reduction associates with basal-like/squamous tumors with increased disease aggressiveness in PDAC patients. This positions ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC. Novelty and ImpactPancreatic ductal adenocarcinoma (PDAC) exhibits heterogeneous molecular subtypes: classical/progenitor and basal-like/squamous. Comprehensive transcriptome and metabolome analyses in the PDAC patient cohorts and PDAC cell lines revealed that elevated ELAPOR1 correlates with enhanced survival, reduced PDAC cell invasion, and a distinct metabolic signature resembling the classical/progenitor subtype. Additionally, 1-methylnicotinamide has been identified as an oncometabolite, showing an inverse correlation with ELAPOR1. These findings emphasize ELAPOR1s potential as a diagnostic and therapeutic target in PDAC. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=118 SRC="FIGDIR/small/558894v1_ufig1.gif" ALT="Figure 1"> View larger version (52K): org.highwire.dtl.DTLVardef@f95c81org.highwire.dtl.DTLVardef@128334corg.highwire.dtl.DTLVardef@3fcb60org.highwire.dtl.DTLVardef@414011_HPS_FORMAT_FIGEXP M_FIG C_FIG HighlightsO_LIELAPOR1 is downregulated in basal-like/squamous PDAC C_LIO_LIUpregulation of ELAPOR1 associates with improved PDAC survival and reduced migration and invasion in PDAC cells C_LIO_LIELAPOR1 expression induces a distinct metabolic signature as characterized by upregulation of lipogenesis and downregulation of amino acid metabolism, commonly observed in the classical/progenitor PDAC subtype C_LIO_LIThe oncometabolite, 1-methylnicotinamide (MNA) is decreased when ELAPOR1 is upregulated, and promotes the migration and invasion of PDAC cells C_LI