PDF(Pubmed)
Abstract：
Pancreatic ductal adenocarcinoma (PDAC) manifests diverse molecular subtypes, including the classical/progenitor and basal-like/squamous subtypes, with the latter known for its aggressiveness. We employed integrative transcriptome and metabolome analyses to identify potential genes contributing to the molecular subtype differentiation and its metabolic features. Transcriptome analysis in PDAC patient cohorts revealed downregulation of adrenoceptor alpha 2A (ADRA2A) in the basal-like/squamous subtype, suggesting its potential role as a candidate suppressor of this subtype. Reduced ADRA2A expression was significantly associated with a high frequency of lymph node metastasis, higher pathological grade, advanced disease stage, and decreased survival among PDAC patients. In vitro experiments demonstrated that ADRA2A transgene expression and ADRA2A agonist inhibited PDAC cell invasion. Additionally, ADRA2A-high condition downregulated the basal-like/squamous gene expression signature, while upregulating the classical/progenitor gene expression signature in our PDAC patient cohort and PDAC cell lines. Metabolome analysis conducted on the PDAC cohort and cell lines revealed that elevated ADRA2A levels were associated with suppressed amino acid and carnitine/acylcarnitine metabolism, which are characteristic metabolic profiles of the classical/progenitor subtype. Collectively, our findings suggest that heightened ADRA2A expression induces transcriptome and metabolome characteristics indicative of classical/progenitor subtype with decreased disease aggressiveness in PDAC patients. These observations introduce ADRA2A as a candidate for diagnostic and therapeutic targeting in PDAC.
摘要：
胰腺导管腺癌（PDAC）表现出不同的分子亚型，包括经典/祖先和基底样/鳞状亚型，后者以其侵略性而闻名。我们采用整合转录组和代谢组分析来鉴定有助于分子亚型分化及其代谢特征的潜在基因。PDAC患者队列中的转录组分析显示，基底样/鳞状亚型中肾上腺素受体α2A（ADRA2A）的下调，提示其作为该亚型的候选抑制因子的潜在作用。ADRA2A表达降低与淋巴结转移的高频率显着相关。病理分级较高，晚期疾病阶段，并降低PDAC患者的生存率。体外实验证明ADRA2A转基因表达和ADRA2A激动剂抑制PDAC细胞侵袭。此外,ADRA2A-high条件下调基底样/鳞状基因表达特征，同时在我们的PDAC患者队列和PDAC细胞系中上调经典/祖细胞基因表达特征。对PDAC队列和细胞系进行的代谢组分析显示，升高的ADRA2A水平与抑制的氨基酸和肉碱/酰基肉碱代谢有关，这是经典/祖先亚型的特征性代谢谱。总的来说，我们的研究结果表明,在PDAC患者中,升高的ADRA2A表达可诱导转录组和代谢组特征,提示经典/祖细胞亚型具有降低的疾病侵袭性.这些观察结果介绍了ADRA2A作为PDAC中诊断和治疗靶向的候选物。
