Abstract
BackgroundLeader 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.MethodsCRISPR 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.ResultsLeader 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.ConclusionsOur 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.
Highlights
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
In this study we have investigated the nature of Leader Cell (LC) in the context of stem-like gene expression and response to chemotherapy
Utilizing our T2A-Green Fluorescent Protein (GFP) cell lines we examined the response of LCs against a panel of chemotherapeutics commonly used to treat ovarian cancer, including olaparib, topotecan, rucaparib, cylcophosphamide, doxorubicin, carboplatin, cisplatin and paclitaxel
Summary
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. Characterised by its asymptomatic progression, over 75% of patients are diagnosed with late stage disseminated disease involving multiple tumor deposits and ascites upon primary presentation [2]. First line treatment options involve surgical debulking and combination platinum and taxane-based chemotherapy, to which most patients initially respond encouragingly [2]. Over 90% of ovarian cancer patients develop recurrent, platinum-resistant disease, limiting therapeutic options and underlying the high mortality rate [3]. There has been minimal improvement to ovarian cancer survival rates since the introduction of platinum-based chemotherapy over 30 years ago [4]. Collective invasion is a fundamental but poorly characterised process common to many metastatic epithelial tumours [6,7,8,9,10]
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