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Journal of Experimental & Clinical Cancer Research

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Open Access 01-12-2021 | Ovarian Cancer | Research

Chemoresistance is mediated by ovarian cancer leader cells in vitro

Authors: Nazanin Karimnia, Amy L. Wilson, Emma Green, Amelia Matthews, Thomas W. Jobling, Magdalena Plebanski, Maree Bilandzic, Andrew N. Stephens

Published in: Journal of Experimental & Clinical Cancer Research | Issue 1/2021

Abstract

Background

Leader cells are a subset of cancer cells that coordinate the complex cell-cell and cell-matrix interactions required for ovarian cancer migration, invasion, tumour deposition and are negatively associated with progression-free survival and response to therapy. Emerging evidence suggests leader cells may be enriched in response to chemotherapy, underlying disease recurrence following treatment.

Methods

CRISPR was used to insert a bicistronic T2A-GFP cassette under the native KRT14 (leader cell) promoter. 2D and 3D drug screens were completed in the presence of chemotherapies used in ovarian cancer management. Leader cell; proliferative (Ki67); and apoptotic status (Cleaved Caspase 3) were defined by live cell imaging and flow cytometry. Quantitative real-time PCR defined “stemness” profiles. Proliferation was assessed on the xCELLigence real time cell analyser. Statistical Analysis was performed using unpaired non-parametric t-tests or one-way ANOVA and Tukey’s multiple comparison post hoc.

Results

Leader cells represent a transcriptionally plastic subpopulation of ovarian cancer cells that arise independently of cell division or DNA replication, and exhibit a “stemness” profile that does not correlate with epithelial-to-mesenchymal transition. Chemotherapeutics increased apoptosis-resistant leader cells in vitro, who retained motility and expressed known chemo-resistance markers including ALDH1, Twist and CD44v6. Functional impairment of leader cells restored chemosensitivity, with leader cell-deficient lines failing to recover following chemotherapeutic intervention.

Conclusions

Our data demonstrate that ovarian cancer leader cells are resistant to a diverse array of chemotherapeutic agents, and are likely to play a critical role in the recurrence of chemo-resistant disease as drivers of poor treatment outcomes.

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Title: Chemoresistance is mediated by ovarian cancer leader cells in vitro
Authors: Nazanin Karimnia
Amy L. Wilson
Emma Green
Amelia Matthews
Thomas W. Jobling
Magdalena Plebanski
Maree Bilandzic
Andrew N. Stephens
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Ovarian Cancer
Ovarian Cancer
Cytostatic Therapy
Published in: Journal of Experimental & Clinical Cancer Research / Issue 1/2021
Electronic ISSN: 1756-9966
DOI: https://doi.org/10.1186/s13046-021-02086-3

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Abstract

Background

Methods

Results

Conclusions

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