Phosphoproteomics of Primary Cells Reveals Druggable Kinase Signatures in Ovarian Cancer.
Phosphoproteomics of Primary Cells Reveals Druggable Kinase Signatures in Ovarian Cancer.
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DOI：
10.1016/j.celrep.2017.03.015
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发表时间：
2017-03-28
期刊：
影响因子：
8.8
通讯作者：
Olsen JV
中科院分区：
文献类型：
--
作者：
Francavilla C;Lupia M;Tsafou K;Villa A;Kowalczyk K;Rakownikow Jersie-Christensen R;Bertalot G;Confalonieri S;Brunak S;Jensen LJ;Cavallaro U;Olsen JV
由于癌症的异质性，我们对癌症的分子决定因素的理解仍然不足。在这里，我们使用上皮性卵巢癌（EOC）作为模型系统，通过基于单次质谱的磷酸化蛋白质组学分析了来自健康或癌组织的少量患者来源的上皮细胞。使用多学科方法，我们证明了原代细胞概括了组织复杂性，并代表了区分癌症与健康细胞的差异表达蛋白和磷酸化位点的有价值来源。此外，我们发现了与EOC相关的激酶特征。特别是，CDK7靶点在EOC原代细胞和卵巢癌细胞系中都有特征。我们发现CDK7控制细胞增殖，CDK7的药理抑制选择性地抑制EOC细胞增殖。我们的方法定义了EOC的分子景观，为患者提供有效的治疗方法铺平了道路。最后，我们强调了磷蛋白质组学在确定癌症临床相关和可药物通路方面的潜力。我们研究了上皮性卵巢癌（EOC）和健康组织，揭示了癌症特异性蛋白和激酶特征的表达。激酶CDK7磷酸化POLR2A并调节EOC细胞增殖。Francavilla等人使用基于质谱的磷酸化蛋白质组学作为揭示癌症特征的有力工具。他们分析了上皮性卵巢癌（EOC）衍生的原代细胞与健康组织相比蛋白质组和磷酸化蛋白质组的变化，并揭示了激酶CDK7在EOC细胞增殖中的作用。
Our understanding of the molecular determinants of cancer is still inadequate because of cancer heterogeneity. Here, using epithelial ovarian cancer (EOC) as a model system, we analyzed a minute amount of patient-derived epithelial cells from either healthy or cancerous tissues by single-shot mass-spectrometry-based phosphoproteomics. Using a multi-disciplinary approach, we demonstrated that primary cells recapitulate tissue complexity and represent a valuable source of differentially expressed proteins and phosphorylation sites that discriminate cancer from healthy cells. Furthermore, we uncovered kinase signatures associated with EOC. In particular, CDK7 targets were characterized in both EOC primary cells and ovarian cancer cell lines. We showed that CDK7 controls cell proliferation and that pharmacological inhibition of CDK7 selectively represses EOC cell proliferation. Our approach defines the molecular landscape of EOC, paving the way for efficient therapeutic approaches for patients. Finally, we highlight the potential of phosphoproteomics to identify clinically relevant and druggable pathways in cancer. We analyze ex-vivo-cultured primary cells using phosphoproteomics We investigate epithelial ovarian cancer (EOC) and healthy tissue We uncover expression of cancer-specific proteins and kinase signatures The kinase CDK7 phosphorylates POLR2A and regulates EOC cell proliferation Francavilla et al. use mass-spectrometry-based phosphoproteomics as a powerful tool to reveal cancer signatures. They analyze changes in the proteome and phosphoproteome of primary cells derived from epithelial ovarian cancer (EOC) compared to healthy tissues and reveal a role for the kinase CDK7 in EOC cell proliferation.