Phosphoproteomics of Primary Cells Reveals Druggable Kinase Signatures in Ovarian Cancer

TY - JOUR

T1 - Phosphoproteomics of Primary Cells Reveals Druggable Kinase Signatures in Ovarian Cancer

AU - Francavilla, Chiara

AU - Lupia, Michela

AU - Tsafou, Kalliopi

AU - Villa, Alessandra

AU - Kowalczyk, Katarzyna

AU - Rakownikow Jersie-Christensen, Rosa

AU - Bertalot, Giovanni

AU - Confalonieri, Stefano

AU - Brunak, Søren

AU - Jensen, Lars J

AU - Cavallaro, Ugo

AU - Olsen, Jesper V

N1 - Copyright © 2017 The Author(s). Published by Elsevier Inc. All rights reserved.

PY - 2017/3/28

Y1 - 2017/3/28

N2 - 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.

AB - 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.

U2 - 10.1016/j.celrep.2017.03.015

DO - 10.1016/j.celrep.2017.03.015

M3 - Journal article

C2 - 28355574

SN - 2211-1247

VL - 18

SP - 3242

EP - 3256

JO - Cell Reports

JF - Cell Reports

IS - 13

ER -