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

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

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Item Type: Article
Status: Published
Official URL: https://doi.org/10.1038/s41416-021-01352-7
Journal or Publication Title: British Journal of Cancer
Volume: 124
Number: 12
Page Range: pp. 1921-1933
Date: 2021
Divisions: Immune Imaging
Depositing User: General Admin
Identification Number: 10.1038/s41416-021-01352-7
ISSN: 0007-0920
Date Deposited: 09 Jun 2021 23:52
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.

Creators:
Creators
Email
Zolghadr, Fatemeh
UNSPECIFIED
Tse, Nigel
UNSPECIFIED
Loka, Dikasya
UNSPECIFIED
Joun, George
UNSPECIFIED
Meppat, Sreelakshmi
UNSPECIFIED
Wan, Victor
UNSPECIFIED
Zoellner, Hans
UNSPECIFIED
Xaymardan, Munira
UNSPECIFIED
Farah, Camile S.
UNSPECIFIED
Lyons, J. Guy
UNSPECIFIED
Hau, Eric
UNSPECIFIED
Patrick, Ellis
UNSPECIFIED
Seyedasli, Naisana
UNSPECIFIED
Last Modified: 09 Jun 2021 23:52
URI: https://eprints.centenary.org.au/id/eprint/1007

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