Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors
Metabolite profiling stratifies pancreatic ductal adenocarcinomas into subtypes with distinct sensitivities to metabolic inhibitors
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DOI：
10.1073/pnas.1501605112
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发表时间：
2015-08-11
影响因子：
11.1
通讯作者：
Evangelista, Marie
中科院分区：
文献类型：
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作者：
Daemen, Anneleen;Peterson, David;Evangelista, Marie
尽管以肿瘤代谢为靶点是一种有前途的治疗策略，但临床上的成功将取决于对具有特定代谢需求的肿瘤亚型的准确诊断。通过广泛的代谢物图谱，我们成功地在胰腺导管腺癌(PDAC)中确定了三种高度不同的代谢亚型。一个亚型被定义为增殖能力降低，而另外两个亚型(糖酵解和产脂)显示出与糖酵解、脂肪生成和氧化还原途径相关的不同代谢物水平，这在转录水平上得到证实。糖酵解和造脂亚型在葡萄糖和谷氨酰胺的利用以及线粒体功能方面表现出显著的差异，这与细胞对糖酵解、谷氨酰胺代谢、脂质合成和氧化还原平衡抑制剂的敏感性不同。在PDAC临床样本中，生脂亚型与上皮型(经典)亚型相关，而糖酵解亚型与间充质(QM-PDA)亚型密切相关，提示在疾病进展中具有功能相关性。对另外200个类似的非PDAC细胞株的药物基因组筛选证实了间质状态与其他肿瘤适应症的代谢药物反应之间的关联。我们的发现强调了广泛的代谢物图谱在预测肿瘤对各种代谢抑制剂的敏感性方面的作用。
Although targeting cancer metabolism is a promising therapeutic strategy, clinical success will depend on an accurate diagnostic identification of tumor subtypes with specific metabolic requirements. Through broad metabolite profiling, we successfully identified three highly distinct metabolic subtypes in pancreatic ductal adenocarcinoma (PDAC). One subtype was defined by reduced proliferative capacity, whereas the other two subtypes (glycolytic and lipogenic) showed distinct metabolite levels associated with glycolysis, lipogenesis, and redox pathways, confirmed at the transcriptional level. The glycolytic and lipogenic subtypes showed striking differences in glucose and glutamine utilization, as well as mitochondrial function, and corresponded to differences in cell sensitivity to inhibitors of glycolysis, glutamine metabolism, lipid synthesis, and redox balance. In PDAC clinical samples, the lipogenic subtype associated with the epithelial (classical) subtype, whereas the glycolytic subtype strongly associated with the mesenchymal (QM-PDA) subtype, suggesting functional relevance in disease progression. Pharmacogenomic screening of an additional similar to 200 non-PDAC cell lines validated the association between mesenchymal status and metabolic drug response in other tumor indications. Our findings highlight the utility of broad metabolite profiling to predict sensitivity of tumors to a variety of metabolic inhibitors.