Clement Emalie J, Law Henry C-H, Qiao Fangfang, Noe Dragana, Trevino Jose G, Woods Nicholas T
Eppley Institute for Research in Cancer and Allied Diseases, Fred & Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Mass Spectrometry and Proteomics Core Facility, University of Nebraska Medical Center, Omaha, NE 68198, USA.
Cancers (Basel). 2022 Apr 13;14(8):1968. doi: 10.3390/cancers14081968.
Pancreatic Ductal adenocarcinoma (PDAC) is an aggressive cancer commonly exhibiting KRAS-activating mutations. Alcohol contributes to the risk of developing PDAC in humans, and murine models have shown alcohol consumption in the context of KRAS mutation in the pancreas promotes the development of PDAC. The molecular signatures in pancreas cells altered by alcohol exposure in the context of mutant KRAS could identify pathways related to the etiology of PDAC. In this study, we evaluated the combined effects of alcohol exposure and KRAS mutation status on the transcriptome and proteome of pancreatic HPNE cell models. These analyses identified alterations in transcription and translational processes in mutant KRAS cells exposed to alcohol. In addition, multi-omics analysis suggests an increase in the correlation between mRNA transcript and protein abundance in cells exposed to alcohol with an underlying KRAS mutation. Through differential co-expression, SERPINE1 was found to be influential for PDAC development in the context of mutant KRAS and ethanol. In terms of PDAC subtypes, alcohol conditioning of HPNE cells expressing mutant KRAS decreases the Inflammatory subtype signature and increases the Proliferative and Metabolic signatures, as we previously observed in patient samples. The alterations in molecular subtypes were associated with an increased sensitivity to chemotherapeutic agents gemcitabine, irinotecan, and oxaliplatin. These results provide a framework for distinguishing the molecular dysregulation associated with combined alcohol and mutant KRAS in a pancreatic cell line model.
胰腺导管腺癌（PDAC）是一种侵袭性癌症，通常表现出KRAS激活突变。酒精会增加人类患PDAC的风险，小鼠模型显示，在胰腺KRAS突变的情况下饮酒会促进PDAC的发展。在突变KRAS背景下，酒精暴露改变的胰腺细胞分子特征可以识别与PDAC病因相关的途径。在本研究中，我们评估了酒精暴露和KRAS突变状态对胰腺HPNE细胞模型转录组和蛋白质组的联合影响。这些分析确定了暴露于酒精的突变KRAS细胞在转录和翻译过程中的改变。此外，多组学分析表明，在存在潜在KRAS突变的情况下，暴露于酒精的细胞中mRNA转录本与蛋白质丰度之间的相关性增加。通过差异共表达分析，发现丝氨酸蛋白酶抑制剂1（SERPINE1）在突变KRAS和乙醇背景下对PDAC发展有影响。在PDAC亚型方面，如我们之前在患者样本中观察到的那样，对表达突变KRAS的HPNE细胞进行酒精预处理会降低炎症亚型特征，并增加增殖和代谢亚型特征。分子亚型的改变与对化疗药物吉西他滨、伊立替康和奥沙利铂的敏感性增加有关。这些结果为在胰腺细胞系模型中区分与酒精和突变KRAS联合作用相关的分子失调提供了一个框架。
