Background and Aims

Proteomics holds promise for individualizing cancer treatment. We analyzed to what extent the proteomic landscape of human colorectal cancer (CRC) is maintained in established CRC cell lines and the utility of proteomics for predicting therapeutic responses.

Methods

Proteomic and transcriptomic analyses were performed on 44 CRC cell lines, compared against primary CRCs (n=95) and normal tissues (n=60), and integrated with genomic and drug sensitivity data.

Results

Cell lines mirrored the proteomic aberrations of primary tumors, in particular for intrinsic programs. Tumor relationships of protein expression with DNA copy number aberrations and signatures of post-transcriptional regulation were recapitulated in cell lines. The 5 proteomic subtypes previously identified in tumors were represented among cell lines. Nonetheless, systematic differences between cell line and tumor proteomes were apparent, attributable to stroma, extrinsic signaling, and growth conditions. Contribution of tumor stroma obscured signatures of DNA mismatch repair identified in cell lines with a hypermutation phenotype. Global proteomic data showed improved utility for predicting both known drug-target relationships and overall drug sensitivity as compared with genomic or transcriptomic measurements. Inhibition of targetable proteins associated with drug responses further identified corresponding synergistic or antagonistic drug combinations. Our data provide evidence for CRC proteomic subtype-specific drug responses.

Conclusions

Proteomes of established CRC cell line are representative of primary tumors. Proteomic data tend to exhibit improved prediction of drug sensitivity as compared with genomic and transcriptomic profiles. Our integrative proteogenomic analysis highlights the potential of proteome profiling to inform personalized cancer medicine.

中文翻译：

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大肠癌细胞系蛋白质组是原发性肿瘤的代表并预测药物敏感性

背景和目标

蛋白质组学有望使癌症治疗个性化。我们分析了人类结直肠癌（CRC）的蛋白质组学现状在建立的CRC细胞系中的维持程度以及蛋白质组学在预测治疗反应中的效用。

方法

对44种CRC细胞系进行了蛋白质组学和转录组学分析，并与原发性CRC（n = 95）和正常组织（n = 60）进行了比较，并与基因组和药物敏感性数据进行了整合。

结果

细胞系反映了原发肿瘤的蛋白质组畸变，特别是对于内在程序。在细胞系中概括了蛋白质表达与DNA拷贝数畸变和转录后调控特征的肿瘤关系。在细胞系中代表了先前在肿瘤中鉴定出的5种蛋白质组学亚型。尽管如此，细胞系和肿瘤蛋白质组之间的系统差异还是很明显的，这归因于基质，外在信号传导和生长条件。肿瘤基质的贡献掩盖了在具有超突变表型的细胞系中鉴定出的DNA错配修复的特征。与基因组或转录组测量结果相比，全球蛋白质组学数据显示，用于预测已知药物-靶标关系和总体药物敏感性的实用性得到了提高。与药物反应有关的可靶向蛋白质的抑制作用进一步确定了相应的协同或拮抗药物组合。我们的数据为CRC蛋白组亚型特异性药物反应提供了证据。

结论

建立的CRC细胞系的蛋白质组是原发性肿瘤的代表。与基因组和转录组谱相比，蛋白质组学数据倾向于表现出更好的药物敏感性预测。我们的综合蛋白质组学分析强调了蛋白质组图谱分析可为个性化癌症医学提供信息的潜力。