Raivola, J., Dini, A., Karvonen, H. et al. Multiomics characterization implicates PTK7 in ovarian cancer EMT and cell plasticity and offers strategies for therapeutic intervention. Cell Death Dis 13, 714 (2022). https://doi.org/10.1038/s41419-022-05161-5
Multiomics characterization implicates PTK7 in ovarian cancer EMT and cell plasticity and offers strategies for therapeutic intervention
|Author:||Raivola, Juuli1; Dini, Alice1; Karvonen, Hanna2;|
1Applied Tumor Genomics, Research Program Unit, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland
2Cancer Signaling, Faculty of Medicine and Health Technology, Tampere University, 33014, Tampere, Finland
3Institute of Biotechnology, University of Helsinki, 00014, Helsinki, Finland
4Research Program in Systems Oncology, Research Program Unit, Faculty of Medicine, University of Helsinki, 00014, Helsinki, Finland
5Institute for Molecular Medicine, FIMM, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, 00014, Helsinki, Finland
6Science for Life Laboratory, Department of Oncology and Pathology, Karolinska Institutet, 17121, Stockholm, Sweden
7Faculty of Biochemistry and Molecular Medicine, University of Oulu, 90014, Oulu, Finland
|Online Access:||PDF Full Text (PDF, 4.5 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe2023031331370
|Publish Date:|| 2023-03-13
Most patients with ovarian cancer (OC) are diagnosed at a late stage when there are very few therapeutic options and a poor prognosis. This is due to the lack of clearly defined underlying mechanisms or an oncogenic addiction that can be targeted pharmacologically, unlike other types of cancer. Here, we identified protein tyrosine kinase 7 (PTK7) as a potential new therapeutic target in OC following a multiomics approach using genetic and pharmacological interventions. We performed proteomics analyses upon PTK7 knockdown in OC cells and identified novel downstream effectors such as synuclein-γ (SNCG), SALL2, and PP1γ, and these findings were corroborated in ex vivo primary samples using PTK7 monoclonal antibody cofetuzumab. Our phosphoproteomics analyses demonstrated that PTK7 modulates cell adhesion and Rho-GTPase signaling to sustain epithelial-mesenchymal transition (EMT) and cell plasticity, which was confirmed by high-content image analysis of 3D models. Furthermore, using high-throughput drug sensitivity testing (525 drugs) we show that targeting PTK7 exhibited synergistic activity with chemotherapeutic agent paclitaxel, CHK1/2 inhibitor prexasertib, and PLK1 inhibitor GSK461364, among others, in OC cells and ex vivo primary samples. Taken together, our study provides unique insight into the function of PTK7, which helps to define its role in mediating aberrant Wnt signaling in ovarian cancer.
Cell death and disease
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
1182 Biochemistry, cell and molecular biology
We would like to thank the patients and their families for participating in the study. We also thank the excellent staff and resources provided by FIMM Technology Centre, FIMM High Throughput Biomedicine Unit and the Proteomics Unit, Institute of Biotechnology & HiLIFE at University of Helsinki. These operations thank Biocenter Finland for instrument funding. We acknowledge the Tampere facility of Virus Production and Tampere facility of Flow Cytometry for their services. This work was funded by Academy of Finland (#333583; #288475; #271845 and Finnish Center of Excellence in Tumor Genetics Research #312042); Academy of Finland decision Profi6 336449 to DU, Sigrid Juselius Foundation, and Finnish Cancer Foundation (to DU, MV, and OK), Emil Aaltonen Foundation and Finnish Cultural Foundation – Pirkanmaa Regional Fund (to HK), the European Union’s Horizon 2020 research and innovation program under grant agreements No 667403 for HERCULES (to SH) and No 965193 for DECIDER (to SH), Knut and Alice Wallenberg Foundation (2015.0291) and Swedish Foundation for Strategic Research SSF (SB16-0058) (to OK) and Swedish Research Council 2021-03420 (to BSL).
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