Moreno Paloma, Ohara Yuuki, Craig Amanda J, Liu Huaitian, Yang Shouhui, Zhang Lin, Panigrahi Gatikrushna, Dorsey Tiffany H, Cawley Helen, Azizian Azadeh, Gaedcke Jochen, Ghadimi Michael, Hanna Nader, Perwez Hussain S
Pancreatic Cancer Section, Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Laboratory of Human Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
bioRxiv. 2024 Mar 13:2024.03.12.584316. doi: 10.1101/2024.03.12.584316.
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. experiments demonstrated that 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.
胰腺导管腺癌（PDAC）表现出多种分子亚型，包括经典/祖细胞亚型和基底样/鳞状亚型，后者以其侵袭性而闻名。我们采用综合转录组和代谢组分析来确定有助于分子亚型分化及其代谢特征的潜在基因。对PDAC患者队列的转录组分析显示，基底样/鳞状亚型中肾上腺素能受体α2A（ADRA2A）表达下调，表明其作为该亚型候选抑制因子的潜在作用。ADRA2A表达降低与PDAC患者淋巴结转移频率高、病理分级高、疾病分期晚及生存率降低显著相关。实验表明，转基因表达和ADRA2A激动剂可抑制PDAC细胞侵袭。此外，在我们的PDAC患者队列和PDAC细胞系中，ADRA2A高表达状态下调了基底样/鳞状基因表达特征，同时上调了经典/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表明，ADRA2A水平升高与氨基酸和肉碱/酰基肉碱代谢受抑制有关，这是经典/祖细胞亚型的特征性代谢谱。总体而言，我们的研究结果表明，ADRA2A表达升高会诱导转录组和代谢组特征，表明PDAC患者中经典/祖细胞亚型的疾病侵袭性降低。这些观察结果将ADRA2A引入作为PDAC诊断和治疗靶点的候选物。
