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Metastasis

A Wnt-mediated phenotype switch along the epithelial–mesenchymal axis defines resistance and invasion downstream of ionising radiation in oral squamous cell carcinoma

Abstract

Background

Dynamic transitions of tumour cells along the epithelial–mesenchymal axis are important in tumorigenesis, metastasis and therapy resistance.

Methods

In this study, we have used cell lines, 3D spheroids and tumour samples in a variety of cell biological and transcriptome analyses to highlight the cellular and molecular dynamics of OSCC response to ionising radiation.

Results

Our study demonstrates a prominent hybrid epithelial–mesenchymal state in oral squamous cell carcinoma cells and tumour samples. We have further identified a key role for levels of E-cadherin in stratifying the hybrid cells to compartments with varying levels of radiation response and radiation-induced epithelial–mesenchymal transition. The response to radiation further entailed the generation of a new cell population with low expression levels of E-cadherin, and positive for Vimentin (ECADLow/Neg-VIMPos), a phenotypic signature that showed an enhanced capacity for radiation resistance and invasion. At the molecular level, transcriptome analysis of spheroids in response to radiation showed an initial burst of misregulation within the first 30 min that further declined, although still highlighting key alterations in gene signatures. Among others, pathway analysis showed an over-representation for the Wnt signalling pathway that was further confirmed to be functionally involved in the generation of ECADLow/Neg-VIMPos population, acting upstream of radiation resistance and tumour cell invasion.

Conclusion

This study highlights the functional significance and complexity of tumour cell remodelling in response to ionising radiation with links to resistance and invasive capacity. An area of less focus in conventional radiotherapy, with the potential to improve treatment outcomes and relapse-free survival.

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Fig. 1: The partial EMT state in OSCC cells and spheroids.
Fig. 2: E-cadherin expression levels determine radiation response and EMT remodelling post-IR.
Fig. 3: The generation of ECADLow/Neg-VIMPos cells post-IR.
Fig. 4: Functional properties of the ECADLow/Neg-VIMpos population.
Fig. 5: Transcriptional dynamics of irradiated SCC25 tumour spheroids and involvement of Wnt signalling pathway.
Fig. 6: Functional involvement of the Wnt signalling pathway in the generation of ECADLow/Neg-VIMPos cells in spheroids, and in radiation response and invasion.

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Acknowledgements

Microscopy analysis, genomics, flow cytometry and irradiation experiments were performed at the Westmead Scientific Platforms, which are supported by the Westmead research hub and Westmead Institute for Medical Research, the Cancer Institute New South Wales and the National Health and Medical Research Council.

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Contributions

F.Z. and N.S. have jointly conceived and executed the project plans and written the manuscript. N.T., D.L., G.J., S.M. and V.W. have contributed to experiments. J.G.L. and E.H. have assisted in the establishment of experimental techniques and in addition to M.X. and H.Z. have had a major intellectual contribution to the project and the resulting manuscript. C.S.F. has provided the human tumour samples and been consulted for subsequent discussions and analyses. E.P. has had major contributions to the bioinformatics analyses and has intellectually contributed to the manuscript. All authors have contributed to the final version of the manuscript.

Corresponding author

Correspondence to Naisana Seyedasli.

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Ethics approval and consent to participate

The ethics protocol for the human OSCC tumour samples was approved by the University of Western Australia human research ethics committee (Protocol #RA/4/1/8562) and written consent from the patient was obtained in accordance with the Declaration of Helsinki.

Data availability

A copy of raw data containing fastq files has been deposited on SRA under BioProject PRJNA611666.

Competing interests

The authors declare no competing interests.

Funding information

This study was supported by the University of Sydney COMPACT research seed grant, Sydney Dental School, University of Sydney, research support and the Dr. Poyner award from Australian Dental Research Foundation (ADRF). F.Z. is supported by the University of Sydney international scholarship. G.J. is funded via a Sydney West Translational Cancer Research Centre (SW-TCRC) Ph.D. Scholarship. Cancer Institute NSW funds SW-TCRC.

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Zolghadr, F., Tse, N., Loka, D. et al. A Wnt-mediated phenotype switch along the epithelial–mesenchymal axis defines resistance and invasion downstream of ionising radiation in oral squamous cell carcinoma. Br J Cancer 124, 1921–1933 (2021). https://doi.org/10.1038/s41416-021-01352-7

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