Pancreatic ductal adenocarcinoma (PDAC) lacks effective treatment options beyond chemotherapy. Although molecular subtypes such as classical and QM (quasi-mesenchymal)/basal-like with transcriptome-based distinct signatures have been identified, deduced therapeutic strategies and targets remain elusive. Gene expression data show enrichment of glycolytic genes in the more aggressive and therapy-resistant QM subtype. However, whether the glycolytic transcripts are translated into functional glycolysis that could further be explored for metabolic targeting in QM subtype is still not known. We used different patient-derived PDAC model systems (conventional and primary patient-derived cells, patient-derived xenografts (PDX), and patient samples) and performed transcriptional and functional metabolic analysis. These included RNAseq and Illumina HT12 bead array, in vitro Seahorse metabolic flux assays and metabolic drug targeting, and in vivo hyperpolarized [1-13C]pyruvate and [1-13C]lactate magnetic resonance spectroscopy (HP-MRS) in PDAC xenografts. We found that glycolytic metabolic dependencies are not unambiguously functionally exposed in all QM PDACs. Metabolic analysis demonstrated functional metabolic heterogeneity in patient-derived primary cells and less so in conventional cell lines independent of molecular subtype. Importantly, we observed that the glycolytic product lactate is actively imported into the PDAC cells and used in mitochondrial oxidation in both classical and QM PDAC cells, although more actively in the QM cell lines. By using HP-MRS, we were able to noninvasively identify highly glycolytic PDAC xenografts by detecting the last glycolytic enzymatic step and prominent intra-tumoral [1-13C]pyruvate and [1-13C]lactate interconversion in vivo. Our study adds functional metabolic phenotyping to transcriptome-based analysis and proposes a functional approach to identify highly glycolytic PDACs as candidates for antimetabolic therapeutic avenues.

中文翻译：

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糖酵解胰腺导管腺癌的功能性无创检测

胰腺导管腺癌 (PDAC) 缺乏化疗以外的有效治疗选择。尽管已经确定了具有基于转录组的不同特征的经典和 QM（准间充质）/基底样等分子亚型，但推断的治疗策略和目标仍然难以捉摸。基因表达数据显示糖酵解基因在更具攻击性和治疗抗性的 QM 亚型中富集。然而，糖酵解转录物是否被翻译成功能性糖酵解，可以进一步探索 QM 亚型中的代谢靶向仍然未知。我们使用了不同的患者来源 PDAC 模型系统（常规和原代患者来源细胞、患者来源异种移植物 (PDX) 和患者样本），并进行了转录和功能代谢分析。这些包括 RNAseq 和 Illumina HT12 珠阵列、体外 Seahorse 代谢通量测定和代谢药物靶向，以及 PDAC 异种移植物中的体内超极化 [1-13C] 丙酮酸盐和 [1-13C] 乳酸磁共振波谱 (HP-MRS)。我们发现糖酵解代谢依赖性在所有 QM PDAC 中都没有明确地在功能上暴露。代谢分析表明，患者来源的原代细胞存在功能性代谢异质性，而与分子亚型无关的常规细胞系则较少。重要的是，我们观察到糖酵解产物乳酸被积极输入到 PDAC 细胞中，并用于经典和 QM PDAC 细胞的线粒体氧化，尽管在 QM 细胞系中更活跃。通过使用 HP-MRS，通过检测最后的糖酵解酶促步骤和体内显着的肿瘤内 [1-13C] 丙酮酸和 [1-13C] 乳酸相互转化，我们能够无创地识别高度糖酵解的 PDAC 异种移植物。我们的研究将功能性代谢表型添加到基于转录组的分析中，并提出了一种功能性方法来鉴定高度糖酵解的 PDAC 作为抗代谢治疗途径的候选者。