Ovarian cancer is characterised by frequent recurrence due to persistent presence of residual cancer stem cells (CSCs). Here, we identify and characterise tumour subsets from ascites-derived tumour cells with stemness, metastasis and metabolic switch properties and to delineate the involvement of pyruvate dehydrogenase kinase 4 (PDK4) in such process.
Ovarian cancer cells/cell lines derived from ascites were used for tumourspheres/ALDH+CD44+ subset isolation. The functional roles and downstream signalling of PDK4 were explored. Its association with clinical outcome of ovarian cancer was analysed.
We demonstrated enhanced CSC characteristics of tumour cells derived from ovarian cancer ascites, concomitant with ALDH and CD44 subset enrichment and high PDK4 expression, compared to primary tumours. We further showed tumourspheres/ALDH+CD44+ subsets from ascites-derived tumour cells/cell lines with CSC properties and enhanced glycolysis. Clinically, PDK4 expression was correlated with aggressive features. Notably, blockade of PDK4 in tumourspheres/ALDH+CD44+ subsets led to inhibition of CSC characteristics, glycolysis and activation of STAT3/AKT/NF-κB/IL-8 (signal transducer and activator of transcription 3/protein kinases B/nuclear factor-κB/interleukin-8) signalling. Conversely, overexpression of PDK4 in ALDH−CD44– subsets exerted the opposite effects.
Ascites-derived ALDH+CD44+ tumour cell subsets endow stemness, metastatic and metabolic switch properties via PDK4-mediated STAT3/AKT/NF-κB/IL-8 signalling, suggesting PDK4 as a viable therapeutic molecular target for ovarian cancer management.
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We thank Ms. Erica Yau and Dr. Emily Pang from Core Facility, for providing and maintaining the equipment needed for flow cytometry.
Ethics approval and consent to participate
Sample collection was under the approval of Human Research Ethics Committee of the University of Hong Kong. Consented patients were informed of the use of their clinical information before sample collection. The authors confirm that they have obtained written consent from each patient to publish the manuscript. The study was performed in accordance with the Declaration of Helsinki. Animal experiments were conducted following protocols approved by the Committee of the Use of Live Animals in Teaching and Research (CULATR) and were carried out under an approved CULATR licence (No. 4598-18).
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This manuscript does not contain any individual person’s data.
The datasets generated and analysed during the current study are available from the corresponding author on reasonable request.
The authors declare no competing interests.
The work was jointly funded by the University of Hong Kong (201711159248) and by the Hong Kong Research Grants Council General Research Fund (HKU 17101414), and the Research Fund from the Department of Obstetrics and Gynaecology.
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Jiang, Y., Siu, M.K., Wang, J. et al. Ascites-derived ALDH+CD44+ tumour cell subsets endow stemness, metastasis and metabolic switch via PDK4-mediated STAT3/AKT/NF-κB/IL-8 signalling in ovarian cancer. Br J Cancer 123, 275–287 (2020). https://doi.org/10.1038/s41416-020-0865-z