Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with distinct molecular subtypes described as classical/progenitor and basal‐like/squamous PDAC. We hypothesized that integrative transcriptome and metabolome 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 additional validation cohorts. Diminished ELAPOR1 expression was linked to high histological grade, advanced disease stage, the basal‐like/squamous subtype, and reduced patient survival in PDAC. In vitro experiments demonstrated that ELAPOR1 transgene expression not only inhibited the migration and invasion of PDAC cells but also induced gene expression characteristics associated with the classical/progenitor subtype. Metabolome 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, a known 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 transcriptome and metabolome 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. These findings position ELAPOR1 as a promising candidate for diagnostic and therapeutic targeting in PDAC.

中文翻译：

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ELAPOR1 诱导经典/祖细胞亚型，并通过胰腺癌代谢重编程降低疾病侵袭性

胰腺导管腺癌 (PDAC) 是一种异质性疾病，具有不同的分子亚型，被描述为经典型/祖型 PDAC 和基底样/鳞状 PDAC。我们假设综合转录组和代谢组方法可以识别候选基因，这些基因的失活有助于侵袭性基底样/鳞状亚型的发展。使用我们的综合方法，我们在 NCI-UMD-German 队列和其他验证队列中确定了内体-溶酶体相关的细胞凋亡和自噬调节因子 1 (ELAPOR1/KIAA1324) 作为候选肿瘤抑制因子。 ELAPOR1 表达减少与高组织学分级、晚期疾病阶段、基底样/鳞状亚型以及 PDAC 患者生存率降低有关。体外实验表明埃拉波尔1转基因表达不仅抑制PDAC细胞的迁移和侵袭，而且诱导与经典/祖细胞亚型相关的基因表达特征。对患者肿瘤和 PDAC 细胞的代谢组分析揭示了与上调的 ELAPOR1 和经典/祖细胞亚型相关的代谢程序，包括上调的脂肪生成和下调的氨基酸代谢。 1-甲基烟酰胺是一种源自 S-腺苷甲硫氨酸的已知致癌代谢物，与 ELAPOR1 表达呈负相关，并在体外促进 PDAC 细胞的迁移和侵袭。综上所述，我们的数据表明，ELAPOR1 表达增强会促进转录组和代谢组特征，这些特征表明经典/祖细胞亚型，而其减少与 PDAC 患者中疾病侵袭性增加的基底样/鳞状肿瘤相关。这些发现使 ELAPOR1 成为 PDAC 诊断和治疗靶向的有希望的候选者。