ELAPOR1 induces the classical/progenitor subtype and contributes to reduced disease aggressiveness through metabolic reprogramming in pancreatic cancer
Authors: Ohara Yuuki , Craig Amanda J. , Liu Huaitian , Yang Shouhui , Moreno Paloma , Dorsey Tiffany H. , Cawley Helen , Azizian Azadeh , Gaedcke Jochen , Ghadimi Michael , Hanna Nader , Ambs Stefan , Hussain S. Perwez 
Published: September 2023

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 vitroexperiments 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 cellsin 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 Impact

Pancreatic 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 ELAPOR1’s potential as a diagnostic and therapeutic target in PDAC.

Graphical abstract

Highlights

ELAPOR1 is downregulated in basal-like/squamous PDAC

Upregulation of ELAPOR1 associates with improved PDAC survival and reduced migration and invasion in PDAC cells

ELAPOR1 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

The oncometabolite, 1-methylnicotinamide (MNA) is decreased when ELAPOR1 is upregulated, and promotes the migration and invasion of PDAC cells