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

• Published in: British journal of cancer 2020-07, Vol.123 (2), p.275-287
• Main Authors: Jiang, Yu-Xin, Siu, Michelle Kwan-Yee, Wang, Jing-Jing, Mo, Xue-Tang, Leung, Thomas Ho-Yin, Chan, David Wai, Cheung, Annie Nga-Yin, Ngan, Hextan Yuen-Sheung, Chan, Karen Kar-Loen
• Format: Article
• Language: English
• Subjects: 631/532/71; 631/67/1517/1709; AKT protein; Aldehyde Dehydrogenase - genetics; Ascites; Ascites - metabolism; Ascites - pathology; Biomedical and Life Sciences; Biomedicine; Cancer Research; CD44 antigen; Cell Line, Tumor; Drug Resistance; Epidemiology; Female; Gene Expression Regulation, Neoplastic - genetics; Glycolysis; Humans; Hyaluronan Receptors - genetics; Interleukin 8; Interleukin-8 - genetics; Kinases; Metabolism; Metastases; Metastasis; Molecular Medicine; Neoplasm Metastasis; Neoplasm Recurrence, Local - genetics; Neoplasm Recurrence, Local - metabolism; Neoplasm Recurrence, Local - pathology; Neoplastic Stem Cells - metabolism; Neoplastic Stem Cells - pathology; NF-kappa B - genetics; NF-κB protein; Oncogene Protein v-akt - genetics; Oncology; Ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Protein kinase; Pyruvate Dehydrogenase Acetyl-Transferring Kinase - genetics; Pyruvic acid; Receptors, Interleukin-8A - genetics; Signal Transduction - genetics; Stat3 protein; STAT3 Transcription Factor - genetics; Stem cells; Transcription; Tumor cell lines; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/s41416-020-0865-z

Background 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. Methods 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. Results 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. Conclusion 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.