Stochastic epithelial-mesenchymal transitions diversify non-cancerous lung cell behaviours

Sugandha Bhatia; Jennifer H Gunter; Joshua T Burgess; Mark N Adams; Kenneth O'Byrne; Erik W Thompson; Pascal Hg Duijf

doi:10.1016/j.tranon.2023.101760

Stochastic epithelial-mesenchymal transitions diversify non-cancerous lung cell behaviours

Transl Oncol. 2023 Nov:37:101760. doi: 10.1016/j.tranon.2023.101760. Epub 2023 Aug 21.

Authors

Sugandha Bhatia¹, Jennifer H Gunter², Joshua T Burgess³, Mark N Adams³, Kenneth O'Byrne⁴, Erik W Thompson³, Pascal Hg Duijf⁵

Affiliations

¹ Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, Woolloongabba 4102, QLD, Australia. Electronic address: s3.bhatia@qut.edu.au.
² Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, Woolloongabba 4102, QLD, Australia; Australian Prostate Cancer Research Centre-Queensland (APCRC-Q), Queensland University of Technology, Woolloongabba 4102, Australia.
³ Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, Woolloongabba 4102, QLD, Australia.
⁴ Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, Woolloongabba 4102, QLD, Australia; Princess Alexandra Hospital, Woolloongabba 4102, QLD, Australia.
⁵ Queensland University of Technology (QUT), School of Biomedical Sciences, Centre for Genomics and Personalised Health at the Translational Research Institute, Woolloongabba 4102, QLD, Australia; Centre for Cancer Biology, Clinical and Health Sciences, University of South Australia and SA Pathology, Adelaide SA, 5001, Australia; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Medical Genetics, Oslo University Hospital, Oslo, Norway. Electronic address: pascal.duijf@unisa.edu.au.

Abstract

Epithelial-mesenchymal plasticity (EMP) is a hallmark of cancer. By enabling cells to shift between different morphological and functional states, EMP promotes invasion, metastasis and therapy resistance. We report that near-diploid non-cancerous human epithelial lung cells spontaneously shift along the EMP spectrum without genetic changes. Strikingly, more than half of single cell-derived clones adopt a mesenchymal morphology. We independently characterise epithelial-like and mesenchymal-like clones. Mesenchymal clones lose epithelial markers, display larger cell aspect ratios and lower motility, with mostly unaltered proliferation rates. Stemness marker expression and metabolic rewiring diverge independently of phenotypes. In 3D culture, more epithelial clones become mesenchymal-like. Thus, non-cancerous epithelial cells may acquire cancer metastasis-associated features prior to genetic alterations and cancerous transformation.

Keywords: Clonal diversity; Epigenetics; Epithelial-mesenchymal plasticity (EMP); Epithelial-mesenchymal transition (EMT); Intra-tumour heterogeneity; Metabolic reprogramming.