title: Phosphoproteomics of Primary Cells Reveals Druggable Kinase Signatures in Ovarian Cancer.
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.
authors.affiliation: 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.
authors.forename: Chiara
authors.initials: C
authors.lastname: Francavilla
authors.affiliation: Unit of Gynecological Oncology Research, Program of Gynecological Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Lupia
authors.affiliation: 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.
authors.forename: Kalliopi
authors.initials: K
authors.lastname: Tsafou
authors.affiliation: Unit of Gynecological Oncology Research, Program of Gynecological Oncology, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Villa
authors.affiliation: Division of Molecular and Cellular Functions, School of Biological Sciences, Faculty of Biology, Medicine and Health, the University of Manchester, Manchester M13 9PL, UK.
authors.forename: Katarzyna
authors.initials: K
authors.lastname: Kowalczyk
authors.affiliation: Proteomics Program, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Blegdamsvej 3B, 2200 Copenhagen, Denmark.
authors.forename: Rosa
authors.initials: R
authors.lastname: Rakownikow Jersie-Christensen
authors.affiliation: Program of Molecular Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Bertalot
authors.affiliation: Program of Molecular Medicine, European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Confalonieri
authors.affiliation: 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.
authors.forename: Søren
authors.initials: S
authors.lastname: Brunak
authors.affiliation: 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.
authors.forename: Lars J
authors.initials: LJ
authors.lastname: Jensen
authors.affiliation: 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.
authors.forename: Ugo
authors.initials: U
authors.lastname: Cavallaro
authors.affiliation: 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.
authors.forename: Jesper V
authors.initials: JV
authors.lastname: Olsen
mesh_terms: D000077216:Carcinoma, Ovarian Epithelial; D004847:Epithelial Cells / Q000378:metabolism; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010750:Phosphoproteins / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D040901:Proteomics / Q000379:methods*; D017381:Spliceosomes / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D009363:Neoplasm Proteins; D010750:Phosphoproteins; D011494:Protein Kinases
keywords: CDK7; EOC; OSE; POLR2A; THZ1; alternative splicing; fimbriae; ovarian cancer; phosphoproteomics; quantitative proteomics