Francavilla Chiara, Lupia Michela, Tsafou Kalliopi, Villa Alessandra, Kowalczyk Katarzyna, Rakownikow Jersie-Christensen Rosa, Bertalot Giovanni, Confalonieri Stefano, Brunak Søren, Jensen Lars J, Cavallaro Ugo, Olsen Jesper V
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
Unit of Gynecological Oncology Research, Program of Gynecological Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
Cell Rep. 2017 Mar 28;18(13):3242-3256. doi: 10.1016/j.celrep.2017.03.015.
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.
由于癌症的异质性，我们对癌症分子决定因素的理解仍然不足。在这里，我们以上皮性卵巢癌（EOC）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微量患者来源的上皮细胞。使用多学科方法，我们证明原代细胞概括了组织复杂性，并且是区分癌症与健康细胞的差异表达蛋白质和磷酸化位点的宝贵来源。此外，我们发现了与EOC相关的激酶特征。特别是，在EOC原代细胞和卵巢癌细胞系中都对CDK7靶点进行了表征。我们表明CDK7控制细胞增殖，并且对CDK7的药理学抑制选择性地抑制EOC细胞增殖。我们的方法定义了EOC的分子格局，为患者的有效治疗方法铺平了道路。最后，我们强调了磷酸化蛋白质组学在识别癌症中临床相关且可药物化途径方面的潜力。
