4.7 Article

Multiomics characterization implicates PTK7 in ovarian cancer EMT and cell plasticity and offers strategies for therapeutic intervention

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CELL DEATH & DISEASE
卷 13, 期 8, 页码 -

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SPRINGERNATURE
DOI: 10.1038/s41419-022-05161-5

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资金

  1. Academy of Finland [333583, 288475, 271845, 312042]
  2. Academy of Finland decision Profi6 [336449]
  3. Sigrid Juselius Foundation
  4. Finnish Cancer Foundation
  5. Emil Aaltonen Foundation
  6. Finnish Cultural Foundation -Pirkanmaa Regional Fund
  7. European Union [667403, 965193]
  8. Knut and Alice Wallenberg Foundation [2015.0291]
  9. Swedish Foundation for Strategic Research SSF [SB16-0058]
  10. Swedish Research Council [2021-03420]
  11. Swedish Foundation for Strategic Research (SSF) [SB16-0058] Funding Source: Swedish Foundation for Strategic Research (SSF)
  12. Swedish Research Council [2021-03420] Funding Source: Swedish Research Council
  13. Academy of Finland (AKA) [271845, 333583, 333583] Funding Source: Academy of Finland (AKA)

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In this study, PTK7 was identified as a potential therapeutic target in ovarian cancer. It was found to modulate cell adhesion and Rho-GTPase signaling, sustain epithelial-mesenchymal transition (EMT) and cell plasticity, and mediate aberrant Wnt signaling. Targeting PTK7 exhibited synergistic activity with chemotherapeutic agents and inhibitors in ovarian cancer, providing a new approach for its treatment.
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-gamma (SNCG), SALL2, and PP1 gamma, 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.

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