Zhang Wen, Wei Yuhong, Ignatchenko Vladimir, Li Lei, Sakashita Shingo, Pham Nhu-An, Taylor Paul, Tsao Ming Sound, Kislinger Thomas, Moran Michael F
Program in Molecular Structure and Function, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
Proteomics. 2014 Mar;14(6):795-803. doi: 10.1002/pmic.201300382.
Nonsmall cell lung cancer (NSCLC) accounts for 85% of lung cancers, and is subdivided into two major histological subtypes: adenocarcinoma (ADC) and squamous cell carcinoma (SCC). There is an unmet need to further subdivide NSCLC according to distinctive molecular features that may be associated with responsiveness to therapies. Four primary tumor-derived xenograft proteomes (two-each ADC and SCC) were quantitatively compared by using a super-SILAC labeling approach together with ultrahigh-resolution MS. Proteins highly differentially expressed in the two subtypes were identified, including 30 that were validated in an independent cohort of 12 NSCLC primary tumor-derived xenograft tumors whose proteomes were quantified by an alternative, label-free shotgun MS methodology. The 30-protein signature contains metabolism enzymes including phosphoglycerate dehydrogenase, which is more highly expressed in SCC, as well as a comprehensive set of cytokeratins and other components of the epithelial barrier, which is therefore distinctly different between ADC and SCC. These results demonstrate the utility of the super-SILAC method for the characterization of primary tissues, and compatibility with datasets derived from different MS-based platforms. The validation of proteome signatures of NSCLC subtypes supports the further development and application of MS-based quantitative proteomics as a basis for precision classifications and treatments of tumors. All MS data have been deposited in the ProteomeXchange with identifier PXD000438 (http://proteomecentral.proteomexchange.org/dataset/PXD000438).
非小细胞肺癌（NSCLC）占肺癌的85%，并细分为两种主要的组织学亚型：腺癌（ADC）和鳞状细胞癌（SCC）。根据可能与治疗反应相关的独特分子特征进一步细分NSCLC存在未满足的需求。通过使用超级稳定同位素标记（super-SILAC）方法结合超高分辨率质谱，对四个原发性肿瘤来源的异种移植蛋白质组（两个ADC和两个SCC）进行了定量比较。鉴定出在两种亚型中高度差异表达的蛋白质，其中30种在一个独立队列的12个NSCLC原发性肿瘤来源的异种移植肿瘤中得到验证，这些肿瘤的蛋白质组通过另一种无标记鸟枪法质谱方法进行定量。这30种蛋白质特征包括代谢酶，如在SCC中表达更高的磷酸甘油酸脱氢酶，以及一组完整的细胞角蛋白和上皮屏障的其他成分，因此ADC和SCC之间明显不同。这些结果证明了超级SILAC方法在原发性组织表征中的实用性，以及与来自不同基于质谱平台的数据集的兼容性。NSCLC亚型蛋白质组特征的验证支持了基于质谱的定量蛋白质组学作为肿瘤精确分类和治疗基础的进一步开发和应用。所有质谱数据已存入蛋白质组交换库，标识符为PXD000438（http://proteomecentral.proteomexchange.org/dataset/PXD000438）。
