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Cell Rep. 2017 Mar 28;18(13):3242-3256. doi: 10.1016/j.celrep.2017.03.015.

Phosphoproteomics of Primary Cells Reveals Druggable Kinase Signatures in Ovarian Cancer.

Author information

1
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark. Electronic address: chiara.francavilla@manchester.ac.uk.
2
Unit of Gynecological Oncology Research, Program of Gynecological Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
3
Disease Systems Biology Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
4
Division of Molecular and Cellular Functions, School of Biological Sciences, Faculty of Biology, Medicine and Health, the University of Manchester, Manchester M13 9PL, UK.
5
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
6
Program of Molecular Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
7
Unit of Gynecological Oncology Research, Program of Gynecological Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy. Electronic address: ugo.cavallaro@ieo.it.
8
Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark. Electronic address: jesper.olsen@cpr.ku.dk.

Abstract

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.

KEYWORDS:

CDK7; EOC; OSE; POLR2A; THZ1; alternative splicing; fimbriae; ovarian cancer; phosphoproteomics; quantitative proteomics

PMID:
28355574
PMCID:
PMC5382236
DOI:
10.1016/j.celrep.2017.03.015
[Indexed for MEDLINE]
Free PMC Article

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